Dissertations / Theses on the topic 'Injury repair'
To see the other types of publications on this topic, follow the link: Injury repair.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Injury repair.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Oryan, Ahmad. "Experimental tendon injury and repair." Thesis, University of Bristol, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260544.
Full text
2
Henderson, Neil C. "Molecular mechanisms of hepatic injury and repair." Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/1554.
Full textAbstract:
In this thesis I examined molecular mechanisms involved in acute and chronic liver injury, and also studied basic pathways mediating tumour promotion. Acute hepatic failure secondary to paracetamol poisoning is associated with high mortality. C-jun (NH2) terminal kinase (JNK) is a member of the mitogen activated protein kinase family and is a key intracellular signaling molecule involved in the control of cell fate. Paracetamol induced hepatic JNK activation in both human and murine paracetamol hepatotoxicity, and in a murine model preceded the onset of hepatocyte death. JNK inhibition in vivo (using two JNK inhibitors with different mechanisms of action) markedly reduced mortality in murine paracetamol hepatotoxicity. In addition, delayed administration of JNK inhibitor was more effective than N-acetylcysteine following paracetamol poisoning in mice. JNK inhibition was not protective in acute carbon tetrachloride or anti-Fas antibody mediated hepatic injury, suggesting specificity for the role of JNK in paracetamol hepatotoxicity. Furthermore, disruption of the JNK1 or JNK2 genes did not protect against paracetamol-induced hepatic damage. Pharmacological JNK inhibition had no effect on paracetamol metabolism, but markedly inhibited hepatic TNF-alpha production following paracetamol poisoning. These data demonstrate a central role for JNK in the pathogenesis of paracetamol induced liver failure, thereby identifying JNK as an important therapeutic target in the treatment of paracetamol hepatotoxicity. Liver fibrosis with loss of tissue architecture and subsequent hepatic failure represents a massive healthcare burden worldwide. Expression of Galectin-3 (a beta-galactoside binding animal lectin) is upregulated in established human fibrotic liver disease, during the development of experimental liver fibrosis and is temporally and spatially related to the induction and resolution of experimental hepatic fibrosis. Disruption of the gene encoding Galectin-3 blocks transdifferentiation of precursors to myofibroblasts in vitro and in vivo, markedly attenuating hepatic scarring in a murine model of liver fibrosis. Inhibition of Galectin-3 expression by siRNA in primary murine and human hepatic stellate cells significantly reduced myofibroblast activation and procollagen(I) expression. The reduction in hepatic fibrosis observed in the Galectin-3-/- mouse occurred despite equivalent liver injury and inflammation, and similar tissue expression of TGF-beta. TGF-beta failed to transactivate Galectin-3-/- hepatic stellate cells, in contrast with wild type hepatic stellate cells. However TGF-beta stimulated signaling via Smad-2 and 3 was equivalent in both Galectin-3-/- and wild type hepatic stellate cells indicating that Galectin-3 is required for TGF-beta mediated myofibroblast activation and matrix production. This supports a novel and important mechanistic role for Galectin-3 in the regulation of myofibroblast activation and consequent liver fibrosis. Finally, in vivo siRNA knockdown of Galectin-3 inhibited myofibroblast activation following hepatic injury and may therefore provide a novel therapeutic approach to the prevention and treatment of liver fibrosis. CD98hc (a ligand for Galectin-3) constitutively and specifically associates with beta1 integrins and is highly expressed on the surface of human tumour cells irrespective of the tissue of origin. CD98hc promotes both anchorage- and serum-independent growth. Using chimeras of CD98hc and the type II membrane protein CD69 demonstrated that the transmembrane domain of CD98hc is necessary and sufficient for integrin association in cells. Furthermore, CD98hc/β1 integrin association is required for focal adhesion kinase-dependent phosphoinositol 3-hydroxykinase activation and cellular transformation. Amino acids 82-87 in the putative cytoplasmic/transmembrane region appear to be critical for the oncogenic potential of CD98hc and provide a novel mechanism for tumour promotion by integrins.
3
Fitton, Anthony Robert. "Muscle recovery following peripheral nerve injury and repair." Thesis, Imperial College London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418071.
Full text
4
Assinck, Peggy Lee. "Myelinating cells in repair of spinal cord injury." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/62788.
Full text
5
Hiebert, Paul Ryan. "Granzyme B in skin aging, injury and repair." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/44226.
Full text
6
Glass, B. J. L. "The role of connexins in tissue injury repair." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1443464/.
Full textAbstract:
Skin integrity is essential for sustaining life and it is important to understand the processes involved in its maintenance and repair. There are several key stages involved in wound healing that rely on the complex communication through gap junctions and their connexins to ensure the resolution of the wound. Gap junctions are expressed in all cells linked with tissue repair and provide a regulated pathway linking the cytoplasm of neighbouring cells and allowing signals to pass freely between the two. In the skin there are three key connexins (Connexins 26, 30 and 43) that undergo dynamic changes and regulate the stages of wound closure. To date, extensive research has shown that inhibiting Cx43 expression can achieve significant improvements in wound repair. Synthetic connexin mimetic peptide Gap27 which possess a conserved homology to the second extracellular loop of Cx43 is now being considered as a candidate to improve the rate of wound repair. At low concentrations Gap27 has been shown to block hemichannels but can target gap junctional intercellular communication at higher concentrations and for longer incubation periods. By using Gap27 as a tool, this thesis explores the importance of connexins, hemichannels and gap junctions in tissue injury and repair. I have dissected out the relative contributions of connexins and their involvement with hemichannels and gap junctions in wound repair while investigating if and how Gap27 reduces other connexins. Further work using in vitro wound healing models has shown how Gap27 can enhance the rate of wound healing in early stages. In the second half of this thesis I continue to use Gap27 to investigate the connexin based communication involved in the spread of cell death and damage during ischemia reperfusion injury in vitro and in vivo. The potential therapeutic implications of the wound healing properties of Gap27 are exciting, novel and promising.
7
Watson, Tim. "The bioelectric correlates of musculoskeletal injury and repair." Thesis, University of Surrey, 1994. http://epubs.surrey.ac.uk/843861/.
Full textAbstract:
There is a need for outcome measurement tools which are able to provide accurate and reliable information regarding the efficiency and efficacy of therapeutic intervention of soft tissue injury e.g. ligament tear. Electrical activity within the body tissues has been shown to be influenced by the tissue state, and following injury, bioelectric changes have been demonstrated for example in bone healing and nerve regeneration. This project considers the relationship between the electrical potentials recorded from the skin surface and clinical recovery following a soft tissue lesion. The measurement of the skin potential is not new but the application and approach used is novel in that a non invasive differential skin surface potential is used instead of the traditional and invasive transcutaneous potential. The differential potential was initially investigated in non injured subjects in order to gain an understanding of its character and behaviour. Simultaneous monitoring of environmental, physiological and psychological factors enabled evaluation of their influence on the generation mechanisms. In order to carry out the work, specialist instrumentation was designed and computer software developed. Injured subjects were recruited during two test series and the results compared with those obtained from the non-injured subjects. Differences in potential profiles were marked on occasions. However a significant percentage of injured subjects presented a profile which was very similar to the non injured subject potentials. The failure to demonstrate consistent differences between potentials from the groups may reflect the lability of tissue potentials or that their behaviour is not purely related to local tissue state. Psychological factors were shown to exert influences on the potentials and differences in environmental and physiological conditions may also be responsible for the variations seen. The refinement of the test apparatus and protocol which is discussed may facilitate more discriminative data collection.
8
Simon, Crystal Michelle. "Investigation of plasma membrane compromise and citicoline-mediated repair after spinal cord injury repair." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/28276.
Full textAbstract:
Thesis (M. S.)--Biomedical Engineering, Georgia Institute of Technology, 2008.Committee Chair: LaPlaca, Michelle; Committee Member: Backus, Deborah; Committee Member: Bellamkonda, Ravi; Committee Member: Lee, Robert; Committee Member: Prausnitz, Mark.
9
Clarke, L. "Endothelial injury and repair in vasculitis of the young." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/17421/.
Full textAbstract:
The vasculitides are a wide spectrum of disorders which are characterised by vascular inflammation. Endothelial injury can occur as a consequence of inappropriate inflammation and is central to the pathogenesis of these varied diseases. This thesis documents the development of assays for detection of novel biomarkers of endothelial injury and/or activation and subsequent reparative responses in children with primary systemic vasculitis. It focuses in particular on circulating endothelial cells, cellular microparticles, growth factors involved in angiogenesis/vasculogenesis and endothelial progenitor cells. Circulating endothelial cells are mature endothelial cells which have become detached from the vessel wall and represent a highly damaged vasculature and were found to be significantly higher in children with active primary systemic vasculitis compared to healthy child controls and patients in remission. Microparticles are released from activated cells, including the endothelium and leukocytes. In this study endothelial and monocyte derived microparticles were found to be elevated during active vasculitis. Growth factors released in response to endothelial injury regulate reparative responses, of which endothelial progenitor cells may play a key role. In this study, patients at disease onset prior to treatment were found to have significantly higher levels of growth factors and endothelial progenitor cells, which decreased with remission inducing therapy. Overall this thesis has investigated the changes in these interlinked biomarkers of injury and repair during active disease, remission and disease flare.
10
Lee, Sena. "ATP and its receptors in nerve injury and repair." Thesis, Queen Mary, University of London, 2013. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8668.
Full textAbstract:
Unlike the peripheral nervous system (PNS), adult neurons in the central nervous system (CNS) have limited regenerative capacity after injury. One interesting phenomenon observed nearly four decades ago was that lesion of a peripheral nerve can significantly enhance the regenerative capacity of the central axons of the corresponding dorsal root ganglion (DRG) neurons, termed a ‘conditioning lesion’, but the underlying mechanism is still not fully understood. Since ATP is released after nerve injury and extracellular ATP has a broad range of biological activities, we postulated that ATP might be the injury signalling molecule that triggers the regenerative machinery in the injured neurons. If that were the case, injection of ATP into a peripheral nerve should be able to mimic the effect of a conditioning lesion. To test this theory, we injected ATP into a peripheral (sciatic) nerve after a dorsal column transection and found that ATP injection did promote the regeneration of injured axons into the lesion cavity. We also found that ATP injection activated transcription factor STAT3 and increased the expression of growth associated protein 43 (GAP43) in the corresponding DRG neurons. ATP injection increased the concentrations of ciliary neurotrophic factor and interleukin-6 in sciatic nerve and DRG. These results indicate that intraneural injection of ATP can mimic conditioning lesion to a certain degree. Most interestingly, we found that a second injection of ATP one week after the first one markedly boosted the effects of the first injection as many more axons grew into or across the lesion compared with double saline injection or ATP plus saline injection. Double ATP injection is also more effective in sustaining the expression of phospho- STAT3 and GAP43. Immunohistochemical analysis showed ATP injection caused little Wallerian degeneration at the injection site. Behavioural tests showed no long-term adverse effects to the injected sciatic nerve. In order to explore the underlying mechanism of ATP induced elevation of the regeneration state of DRG neurons and look for more potent purinoceptor agonists to stimulate axonal regeneration, we first tried to identify the expression of purinoceptor subtypes in sciatic nerves using quantitative PCR and immunohistochemistry. We found that mRNAs for all the four P1 and fourteen P2 purinoceptor subtypes were expressed in the sciatic nerve, DRG or dissociated Schwann cells at various levels. Immunohistochemical analysis showed that purinoceptor subtypes are expressed by different types of cells. Due to the expression of nearly all purinoceptor subtypes in the sciatic nerve, it will be a big challenge to identify the receptor subtype(s) responsible for ATP induced axonal regeneration. We have set up a compartmented co-culture system to test various agonists/antagonists of purinoceptors. Taken together, we have shown that intraneural ATP injection can mimic conditioning lesion in promoting sensory axonal regeneration. Identification of the receptor subtype(s) and other molecules involved in the enhanced regeneration capacity of injured neurons may lead to the development of therapeutic agents to effectively promote the axonal regeneration of both peripheral and central neurons.
11
Eleftheriou, D. "Endothelial injury and repair in childhood arterial ischaemic stroke." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1378547/.
Full textAbstract:
Abnormalities of the cervical or intracranial circulation, termed arteriopathies are the leading mechanism of both cause and recurrence of childhood arterial ischaemic stroke (AIS). Approximately 20% of children with AIS will have stroke recurrence but there are currently no robust biomarkers to identify this high risk group, and hence identification of patients who may be amenable to secondary preventative strategies has not been possible. This thesis attempts to address this unmet need by studying novel biomarkers to distinguish patients at risk of stroke recurrence. Indices of endothelial injury, repair and hypercoagulability were compared between patients with recurrent clinical disease course and children with a single event. Circulating endothelial cells (CECs) were higher in children with recurrent AIS, compared to those with no recurrence and controls. Further evidence of endothelial injury and cellular activation was derived by examining circulating microparticles (MP) profiles. Plasma from patients with AIS recurrence contained increased numbers of endothelial, platelet and neutrophil derived MP compared to those with no recurrence. These MPs were highly prothrombotic due to phosphatidylserine exposure providing a platform for the assembly and activation of coagulation factors; and also expression of tissue factor on some MP. An efficient in vitro assay to assess MP-related hypercoagulability by quantifying MP-mediated thrombin generation was established. Children with recurrent AIS were shown to have an enhanced MP-mediated thrombin generation. Lastly, a disturbance in endothelial progenitor cells (EPCs) in children with AIS recurrence was observed suggesting that there could be impairment of endothelial repair in these patients. In conclusion, despite the wide spectrum of clinical and radiological presentation of childhood AIS, the studies undertaken in this thesis suggest that there is an unfavourable imbalance between endothelial injury and repair, and excess hypecoagulability in children with recurrent AIS. These novel observations provide unique insights into the pathophysiology of paediatric AIS.
12
Kraemer, Marina. "Novel scaffolds for spinal cord repair." Thesis, University of Bath, 2013. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.591041.
Full textAbstract:
Injuries to the central nervous system (CNS) have traumatic consequences such as irreparable disability due to the inability of the CNS to regenerate injured nerve fibres. The aim of the work presented here was to develop a scaffold which potentially provides guidance to axons in the injured spinal cord thus facilitating signal transduction. A poly-(lactic-co-glycolic acid) (PLGA, PLA:PGA ratio of 75:25) flat sheet membrane scaffold was created using phase inversion with N-methyl pyrrolidinone (NMP) as the solvent and water as the non-solvent for immersion precipitation. PLGA flat sheet membranes were exposed to surface treatments including aminolysis, peptide immobilisation and ozonation in order to achieve higher cell attachment of PC12 cells, a cell line which was cloned from a solid pheochromocytoma tumour of white rats, and used as a tool for measurement of regeneration. Cell attachment studies revealed no significant difference in cell attachment between modified and not-modified PLGA flat sheet membranes. However, the absence of foetal calf serum (FCS) resulted in fivefold higher cell attachment compared to medium supplemented with 10% FCS. A second scaffold was produced by electrospinning 10% (w/w) PLGA in a chloroform:methanol (CHCl3:MeOH) mixture in ratio of 3:1 resulting in a nanofibrous scaffold. Optimum settings for electrospinning were found to be 3 ml/h feeding rate, 15kV applied voltage and 11cm collector-to-needle distance. Random and aligned PLGA nanofibres were produced, with a fibre diameter of 530±140nm. PC12 cells attached and differentiated to the nanofibrous scaffold. When exposed to NGF these cells stopped dividing and extended neurites. On random fibres, neurite orientation was random, whereas on aligned fibres 63% of neurites grew with the fibre orientation ±15��ᵒ. After 7 days of exposure to NGF, cells had 1-4 neurites on random fibres, reaching a maximum length of 188μm, whereas on aligned fibres, cells had 1-2 neurites, reaching a maximum length of 400μm. PLGA nanofibres were also investigated as a delivery vehicle for bioactive molecules. For this, poly-L-lysine (PLL) was incorporated into electrospun PLGA nanofibres via emulsion electrospinning. PLGA-PLL nanofibres were significantly larger than PLGA nanofibres having a diameter of 830±190nm. In order to visualise the incorporation of PLL, FITC-PLL was electrospun und the resulting nanofibres fluoresced greed. Attachment of PC12s to PLGA-PLL nanofibres was not significantly different compared to PLGA nanofibres. Aligned PLGA-PLL nanofibres were shown to promote neurite outgrowth of PC12s with resulting neurites of up to twice the length compared to aligned PLGA nanofibres. The results suggest that PLGA nanofibres strongly influences neurite organisation, which is potentially useful for future therapeutic approaches. The work in this thesis has shown that electrospun PLGA nanofibre mats have the potential to be used as scaffolds for spinal cord repair addressing topographical guidance and delivery of bioactive molecules to the site of injury.
13
Jergović, Davor. "Facial nerve injury and microsurgical repair : experimental and clinical studies /." Linköping : Univ, 2002. http://www.bibl.liu.se/liupubl/disp/disp2002/med716s.pdf.
Full text
14
Mohammed, Salman Afroze Azmi. "Modulation of myocardium repair after ischemic injury : role of macrophages." Thesis, Open University, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.580134.
Full textAbstract:
Macrophages are primary responders that are involved in regulation of left ventricular remodeling post myocardial infarct (MI) at various levels. Macrophage role post ischemia can be best studied by eliminating or blocking their population and also by increasing their numbers, and determining the outcome. Four different approaches to modulate macrophage number or activity have been used: a) human diphtheria toxin receptor (hDTR) transgenic mice; b) injection with clodronate liposomes (CL) in C57 mice; c) pharmacologic blockade of TLR4 which is expressed also in macrophages; d) selection of Ml or inflammatory macrophages, by adoptive transfer of NF-kB P50-/- bone marrow (BM).
15
Cawardine, Darren Rhys. "Engineering canine olfactory ensheathing cells for spinal cord injury repair." Thesis, University of Bristol, 2017. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.738207.
Full text
16
singh, Shilpa. "ONCOGENE INDUCED DNA REPLICATION IN LUNG INJURY REPAIR AND CARCINOGENESIS." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5362.
Full textAbstract:
Deregulation of genome duplication is a common theme in cancer cells. Although multitude of pathways has been discovered and implicated in the ability of oncogenes or loss of function tumor suppressors to induce oncogenesis, most of the pathways ultimately converge in deregulated genome duplication or uncoupling of DNA replication and segregation in cancer cells. It is important to determine how known oncogenes deregulate genome duplication, and if prevention of deregulated genome duplication could be a feasible target to thwart uncontrolled proliferation of cancer cells. Conventional paradigm ascribes the cell proliferative function of the human oncoprotein mouse double minute2 (MDM2) primarily to its ability to degrade p53. Here we demonstrate that in the absence of p53, MDM2 induces replication stress eliciting an early S-phase checkpoint response to inhibit further firing of DNA replication origins. Our data uncovers a novel pathway, defended by the intra-S-phase checkpoint, by which MDM2 induces unscheduled origin firing and accelerates S-phase entry of cells in the absence of p53. To identify cell proliferative events consequent to MDM2 overexpression in noncancerous lung, transgenic mice expressing human MDM2 in either lung Club or alveolar cells after doxycycline (Dox) treatment were generated. Dox-induced MDM2 expression considerably increased the frequency of DNA replicating Club or alveolar cells after naphthalene or radiation-induced lung injury, and clonal expansion of lung progenitor cells accelerating restoration of the lost epithelial layer.
Gain of function (GOF) p53 mutations, observed frequently in most intractable human cancers, establish dependency for tumor maintenance and progression. We show that GOF p53 increases DNA replication origin firing, stabilizes replication forks, and promotes micronuclei formation, thus facilitating the proliferation of cells with genomic abnormalities. Following genome-wide analyses utilizing ChIP-Seq and RNA-Seq, GOF p53-induced origin firing, micronuclei formation and fork protection were traced to the ability of GOF p53 to transactivate Cyclin A and Chk1. Highlighting the therapeutic potential of Chk1’s role in GOF p53 dependency, experiments in cell culture and mouse xenografts demonstrated that inhibition of Chk1 selectively blocked proliferation of cells and tumors expressing GOF p53. Our data suggest the exciting possibility that checkpoint inhibitors could efficiently and selectively target cancers expressing GOF p53 alleles.
17
Pettersson, Jonas. "Biosynthetic conduits and cell transplantation for neural repair." Doctoral thesis, Umeå universitet, Institutionen för integrativ medicinsk biologi (IMB), 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-42440.
Full textAbstract:
Spinal cord injury results in complete failure of the central neurons to regenerate and is associated with cyst formation and enlargement of the trauma zone. In contrast to the spinal cord, axons in the injured peripheral nerve have the capacity to undergo some spontaneous regeneration. However, significant post-traumatic loss of nervous tissue causing long nerve gap is one of the main reasons for the poor restoration of function following microsurgical repair of injured nerves. The present thesis investigates the effects of biodegradable conduits prepared from fibrin glue and poly-beta-hydroxybutyrate (PHB) in combination with cultured Schwann cells, mesenchymal stem cells and extracellular matrix molecules on regeneration after spinal cord and peripheral nerve injury in adult rats. At 4-8 weeks after transplantation into the injured spinal cord, the PHB conduit was well integrated into the cavity but regenerating axons were found mainly outside the PHB. When suspension of BrdU-labeled Schwann cells was added to the PHB, regenerating axons filled the conduit and became associated with the implanted cells. Modification of the PHB surface with extracellular matrix molecules significantly increased Schwann cell attachment and proliferation but did not alter axonal regeneration. To improve the labeling technique of the transplanted cells, the efficacy of fluorescent cell tracers Fast Blue, PKH26, Vibrant DiO and Cell Tracker™ Green CMFDA was evaluated. All tested dyes produced very efficient initial labeling of olfactory ensheathing glial cells in culture. The number of Fast Blue-labeled cells remained largely unchanged during the first 4 weeks whereas the number of cells labeled with other tracers was significantly reduced after 2 weeks. After transplantation into the spinal cord, Fast Blue-labeled glial cells survived for 8 weeks but demonstrated very limited migration from the injection sites. Additional immunostaining with glial and neuronal markers demonstrated transfer of the dye from the transplanted cells to the host tissue. In a sciatic nerve injury model, the extent of axonal regeneration through a 10mm gap bridged with tubular PHB conduit was compared with a fibrin glue conduit. At 2 weeks after injury, the fibrin conduit supported similar axonal regeneration and migration of the host Schwann cells compared with the PHB conduit augmented with a diluted fibrin matrix and GFP-labeled Schwann cells or mesenchymal stem cells. The long-term regenerative response was evaluated using retrograde neuronal labeling. The fibrin glue conduit promoted regeneration of 60% of sensory neurons and 52% of motoneurons when compared with the autologous nerve graft. The total number of myelinated axons in the distal nerve stump in the fibrin conduit group reached 86% of the nerve graft control and the weight of gastrocnemius and soleus muscles recovered to 82% and 89%, respectively. When a fibrin conduit was used to bridge a 20mm sciatic nerve gap, the weight of gastrocnemius muscle reached only 43% of the nerve graft control. The morphology of the muscle showed more chaotic appearance and the mean area and diameter of fast type fibers were significantly worse than those of the corresponding 10mm gap group. In contrast, both gap sizes treated with nerve graft showed similar fiber size. In summary, these results show that a PHB conduit promotes attachment, proliferation and survival of adult Schwann cells and supports marked axonal growth after transplantation into the injured spinal cord. The data suggest an advantage of the fibrin conduit for the important initial phase of peripheral nerve regeneration and demonstrate potential of the conduit to promote long-term neuronal regeneration and muscle recovery.
18
Dabbagh, Karim. "Effect of thrombin and alpha-1-antitrypsin on mesenchymal cell proliferation and procollagen production." Thesis, University College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285383.
Full text
19
Li, Ruifu. "A Novel Thiolated Hyaluronic acid Hydrogel for Spinal Cord Injury Repair." Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31410.
Full textAbstract:
Spinal Cord Injury (SCI) often causes cell death, demyelination, axonal degeneration and cavitation, resulting in functional motor and sensory loss below the site of injury. In an attempt to overcome SCI, the regenerating neurons require a permissive environment to promote their ability to reconnect. We report a novel thiolated hyaluronic acid (HA) hydrogel scaffold that can be used to repair the injured spinal cord. More specifically, thiolated hyaluronic acid hydrogels with varying thiol concentrations were successfully synthesized. The amount of thiol groups was measured spectrophotometrically using Ellman’s test. HA gels with different crosslinking densities were synthesized and the water content of the hydrogels was determined. The thermal behavior of the HA gels were studied by DSC. The strength of the hydrogels with varying thiol group content was evaluated by a rheometer. In addition, in vitro enzymatic degradation was performed through submerge the hydrogels in 200U/ml of hyaluronidase solution and incubate at 37°C. According to the result of the present study, this novel hydrogel shows great potential to serve as a 3D cell-patterning scaffold which can be inserted into a hollow fiber channel that could be used to promote regeneration after the SCI.
20
Erschbamer, Matthias. "Spinal cord injury : development of protection and repair strategies in rats /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-267-5/.
Full text
21
Dunster, Joanne L. "Mathematical models of soft tissue injury repair : towards understanding musculoskeletal disorders." Thesis, University of Nottingham, 2012. http://eprints.nottingham.ac.uk/27797/.
Full textAbstract:
The process of soft tissue injury repair at the cellular lew I can be decomposed into three phases: acute inflammation including coagulation, proliferation and remodelling. While the later phases are well understood the early phase is less so. We produce a series of new mathematical models for the early phases coagulation and inflammation. The models produced are relevant not only to soft tissue injury repair but also to the many disease states in which coagulation and inflammation play a role. The coagulation cascade and the subsequent formation of the enzyme thrombin are central to the creation of blood clots. By focusing on a subset of reactions that occur within the coagulation cascade, we develop a model that exhibits a rich asymptotic structure. Using singular perturbation theory we produce a sequence of simpler time-dependent model which enable us to elucidate the physical mechanisms that underlie the cascade and the formation of thrombin. There is considerable interest in identifying new therapeutic targets within the coagulation cascade, as current drugs for treating pathological coagulation (thrombosis) target multiple factors and cause the unwelcome side effect of excessive bleeding. Factor XI is thought to be a potential therapeutic target, as it is implicated in pathological coagulation but not in haemostasis (the stopping of bleeding), but its mechanism of activation is controversial. By extending our previous model of the coagulation cascade to include the whole cascade (albeit in a simplistic way) we use numerical methods to simulate experimental data of the coagulation cascade under normal as well as specific-factor-deficient conditions. We then provide simulations supporting the hypothesis that thrombin activates factor XI. The interest in inflammation is now increasing due to it being implicated in such diverse conditions as Alzmeimer's disease, cancer and heart disease. Inflammation can either resolve or settle into a self-perpetuating condition which in the context of soft tissue repair is termed chronic inflammation. Inflammation has traditionally been thought gradualIy to subside but new biological interest centres on the anti-inflammatory processes (relating to macrophages) that are thought to promote resolution and the pro-inflammatory role that neutrophils can provide by causing damage to healthy tissue. We develop a new ordinary differential equation model of the inflammatory process that accounts for populations of neutrophils and macrophages. We use numerical techniques and bifurcation theory to characterise and elucidate the physiological mechanisms that are dominant during the inflammatory phase and the roles they play in the healing process. There is therapeutic interest in modifying the rate of neutrophil apoptosis but we find that increased apoptosis is dependent on macrophage removal to be anti-inflammatory. We develop a simplified version of the model of inflammation reducing a system of nine ordinary equations to six while retaining the physical processes of neutrophil apoptosis and macrophage driven anti-inflammatory mechanisms. The simplified model reproduces the key outcomes that we relate to resolution or chronic inflammation. We then present preliminary work on the inclusion of the spatial effects of chemotaxis and diffusion.
22
Emerson, Barry Sean. "Targeting hydrogen sulfide breakdown for regulation of myocardial injury and repair." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/17947.
Full textAbstract:
Hydrogen sulfide (H2S) is an endogenous gasotransmitter that regulates vascular function and blood pressure, and also protects the heart from injury associated with myocardial infarction (MI). The mitochondrial enzyme thiosulfate sulfurtransferase (TST) has a putative role in the breakdown of H2S but its role in the cardiovascular system is unknown. I hypothesised that TST reduces cardiovascular H2S availability and that inhibiting TST activity may therefore ameliorate cardiovascular pathology. In the heart, TST was expressed by cardiomyocytes and vascular smooth muscle cells. Tst-/- mice all survived to adulthood and had normal cardiac structure and function. Cardiac and hepatic H2S breakdown rates were reduced and H2S levels were higher in the blood of Tst-/- mice. However, in heart tissue, protein levels for the H2S-activated Nrf2 downstream targets, thioredoxin (Trx1) and heme oxygenase-1 (HO-1) were comparable. In contrast, protein levels for the cardiac specific H2S-synthetic enzyme, cystathionine gamma lyase (CSE) was reduced, suggesting a homeostatic negative feedback mechanism to maintain H2S at non-toxic levels. Respiration, measured using an oxygen-sensing electrode was normal in isolated mitochondria from whole Tst-/- compared to control C57BL6 hearts. Endothelial nitric oxide synthase (eNOS) protein expression was lower in Tst-/- hearts, highlighting potential cross talk between H2S and nitric oxide (NO) signalling. TST was expressed in whole aorta homogenates and in isolated endothelial cells from aorta and small intramuscular vessels of the hindlimb from C57BL/6N control mice. Myography and western blotting revealed a greater influence of NO in aorta from Tst-/- mice that was associated with increased phosphorylation of the activating serine1177 residue of eNOS (PeNOSSer1177). NO plays a lesser role in resistance arteries, but in comparison to control vessels, small mesenteric vessels from Tst-/- mice was more reliant on small and intermediate calcium activated potassium channels for relaxation. Tst-/- mice were normotensive, despite this alteration in the regulation of vascular tone. However, metabolic cage experiments identified that Tst-/- mice presented with diuresis, polydipsia, and increased urinary electrolyte excretion of sodium, potassium and chloride, possibly to compensate for increased vascular tone in order to maintain stable blood pressure. To investigate the role of TST in regulating the response to pathological challenge, MI was induced by coronary artery ligation (CAL). In control mice, gene expression of CSE was downregulated by 2 days after CAL, but TST expression was 12-fold increased, suggesting regulation of H2S bioavailability during the acute MI-healing phase. Tst-/- male mice had a 40% greater incidence of cardiac rupture during infarct healing and surviving Tst-/- mice had greater left ventricular dilatation and impaired function compared to controls. Ex vivo, isolated perfused hearts from Tst-/- mice were more susceptible to ischaemia/ reperfusion injury, suggesting an additional role of TST in determining cardiomyocyte susceptibility to injury. In conclusion, these data indicate that cardiovascular H2S bioavailability is regulated through degradation by TST. The data presented here provide evidence for significant tissue specific crosstalk between H2S synthetic and degradative mechanisms and between H2S and other local regulatory mechanisms, including ion channels and NOS. We infer TST has a physiological role in the kidney where its loss leads to changes in renal electrolyte and water handling, although other compensatory mechanisms prevent a change in blood pressure. Under conditions of pathological challenge following MI, loss of TST is detrimental, illustrating its key role in removal of H2S. The data refute the original hypothesis that TST inhibition would be protective against cardiovascular pathology. Further studies in mice with tissue specific deletion of TST are now required to more fully reveal the cardiovascular role of TST.
23
Hidalgo, San Jose Lorena. "Microfluidic production of stem-cell microcapsules for spinal cord injury repair." Thesis, Cardiff University, 2017. http://orca.cf.ac.uk/99333/.
Full textAbstract:
Stem cell therapy demonstrates much promise for the replacement of damaged tissue in several diseases, including spinal cord injury. However, challenges around the control of stem cell fate in situ still hinders effective recovery of the normal tissue function. Stem cell encapsulation permits their immobilization within biocompatible scaffolds, allowing for a better control of parameters such as proliferation, integration, migration and differentiation within the host tissue. A customized microfluidic device was developed for the production of alginate microcapsules. The diameter of such microcapsules could be easily controlled by the modification of the fluids flow rates, allowing for the reproducible production of highly monodisperse microcapsules. This microfluidic method was then successfully applied for the encapsulation of two different types of stem cells: (i) Neural Stem Cells and (ii) Dental Pulp Stem Cells. Both cell types demonstrated survival within the alginate microcapsules for up to three weeks in culture. However, an early egress of cells from inside to outside of the microcapsules was observed 3 days post-encapsulation. In order to delay such cell escape, alginate microcapsules were modified through the addition of type I collagen. The alginate-collagen microcapsules permitted similar rates of cell survival and permitted the delay of cell egress until 10 days after encapsulation. Stem cells demonstrated a retention of their stem cell and neuronal differentiation properties upon selective release from alginate-collagen microcapsules, as demonstrated by high proliferation rates and the production of stem cell and neuronal markers. When cell-laden microcapsules were transplanted into an ex vivo SCI model the microcapsules were able to effectively retain the transplanted stem cells at the site of implantation. Transplanted cells survived up to 10 days in culture after transplantation and demonstrated the production of neuronal markers within the cord cultures. The results presented in this thesis demonstrate the ability of stem cells to retain their viability and neuronal differentiation capacity within alginate-collagen microcapsules, thereby providing a promising future therapy for the treatment of spinal cord injury.
24
Lenihan, David V. "New methods for the repair and assessment of peripheral nerve injury." Thesis, University of Edinburgh, 2001. http://hdl.handle.net/1842/22406.
Full textAbstract:
The present study was designed to investigate factors which could influence the regeneration of peripheral nerves which had been cut and repaired using a variety of grafting techniques. These methods were: repair with a microwaved muscle autograft, a freeze-thawed muscle autograft, and several groups where repair involved a controlled release biodegradable glass tube containing a variety of factors which have been shown to influence nerve regeneration. Assessment of all of these experimental groups involved the use of established electrophysiological and morphometric techniques but also the development of new techniques for measuring the conduction velocity of the lowest fibres and the variability of reinnervation at the neuromuscular junction (stimulated jitter). The experiments revealed that the microwave muscle graft provided the structural support needed for regeneration, however difficulties in preparing the graft made its use in the clinical setting doubtful. The controlled release glass tube did not interfere with regeneration an supported similar levels of regeneration when compared with an established surgical technique. Jitter proved to be an excellent and highly discriminatory test for assessment of the progression and quality of reinnervation of skeletal muscle. The potential for using these techniques in the experimental and clinical settings is discussed.
25
Dimarakis, Ioannis. "A novel CD34 stem cell subpopulation for ischaemic myocardial injury repair." Thesis, Imperial College London, 2008. http://hdl.handle.net/10044/1/8409.
Full text
26
Kimpton, Amanda-Jane. "Comparative structural analysis of reinnervated muscle following nerve injury and repair." Thesis, University of Edinburgh, 2002. http://hdl.handle.net/1842/23076.
Full textAbstract:
The repair of peripheral nerve injuries is a major reconstructive problem, particularly when direct suturing of a transected nerve is not feasible option. This arises because mechanisms of nerve repair are not fully understood. The purpose of the first group of experiments was to compare methods of nerve repair, including use of novel, biodegradable glass tubes. The possible use of these tubes as a means of confining humoral or cellular substances at the site of repair was also assessed. In a further study, experiments were designed to establish first, the optimal timing of nerve repair (immediate or delayed); second, whether there was a difference in the level of recovery between neonates and adults after nerve repair; third, to assess the freeze-thawed muscle graft (FTMG) method as a surgical technique and to determine whether the FTMG is at least as good as a conventional nerve graft. This investigation was carried out in an animal model of obstetrical brachial plexus palsy (OBPP). Assessment of experimental outcome in both studies was by measurement of the structural and cytochemical changes which occurred in the target muscle after peripheral nerve injury and repair. Morphometric, histochemical and immunocytochemical measurements showed alterations in muscle fibre size and architecture, as well as connective tissue content and the proportions and the distributions of the different fibre types. These changes indicated that after repair with controlled-release glass tubes there was reinnervation of the target muscle, although the results were superior after repair by FTMG. As to whether the potential of nerve to regenerate after repair decreases with age, or whether immediate or delayed repair is best in the treatment of OBPP, the experiments have contributed to solving but have not resolved the dilemma associated with these issues.
27
Chaggar, Parminder. "Plasma cytokines and markers of remodeling in myocardial injury and repair." Thesis, University of Manchester, 2018. https://www.research.manchester.ac.uk/portal/en/theses/plasma-cytokines-and-markers-of-remodeling-in-myocardial-injury-and-repair(ea82d837-8825-4f1e-ac75-890458294eff).html.
Full textAbstract:
Introduction: The heart failure (HF) phenotype is associated with multiple pathological changes at the cellular/biochemical level but this is not always a permanent state, despite sometimes extremely severe clinical and echocardiographic features. However, the underlying molecular and inflammatory processes are incompletely understood and often, contradictory effects are reported. This study examines a wide array of plasma pro-inflammatory markers and remodeling proteins in experimentally induced HF and recovery. Methods: Plasma IFNÎ3, CXCL-9, IP-10, IL-21, IL-17A, TNFα, decorin, sFRP-3 and VEGF-A patterns were assessed in a series of ovine models; 8 sheep that underwent tachypaced-induced HF and recovery with cessation of pacing (Recovery group); 7 sheep that underwent tachypaced-induced asymptomatic LV dysfunction and subsequent treatment with tadalafil to prevent clinical deterioration in the context of continued tachypacing (Tadalafil sheep); and 5 sheep that underwent acute myocardial ischaemia-reperfusion injury (MI group). Baseline inflammatory profiles and remodeling proteins were validated in a separate cohort of 10 healthy sheep that underwent a comprehensive frailty assessment. Results: There was a borderline inverse association between IFNÎ3 with clinical HF in the Recovery group but no correlation with LV function. High baseline levels of pro-inflammatory cytokines did not impact on susceptibility to, severity of, or recovery from HF in sheep exposed to tachycardic pacing. Furthermore, plasma decorin increases significantly with tachypaced-HF and remains elevated despite improved LV function or tadalafil treatment. Conclusion: The present study has examined a broad inflammatory profile in HF and recovery, including those mediated via TH1 (IFNÎ3, CXCL-9 and IP-10), TH2 (IL-21), TH17 (IL-17A) and monocyte (TNFα) cell lineages. The findings demonstrate that systemic inflammation has no impact on susceptibility to, severity of, or recovery from HF in sheep exposed to tachycardic pacing. The findings of this study may draw into question whether the immune system plays a pivotal role in HF disease progression and severity although further research is required before definitive conclusions can be secured. Furthermore, this study demonstrates plasma decorin increases significantly with the development of HF. This may represent a physiological response to attenuate the effects of adverse remodeling in HF. This is the first study to demonstrate temporal changes in plasma decorin during both myocardial injury and recovery in a large mammal. Decorin may serve as a biomarker of myocardial injury and could be a target for therapeutic manipulation. These findings require validation in a larger series.
28
Ting, Wei-tsyi. "Studies on the death, injury, repair of injury, and the detection of Salmonella subjected to freezing and thawing /." The Ohio State University, 1986. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487267546984344.
Full text
29
Hart, Geoffrey. "The effect of therapeutic ultrasound on wound repair with emphasis on fibroblast activity." Thesis, King's College London (University of London), 1993. https://kclpure.kcl.ac.uk/portal/en/theses/the-effect-of-therapeutic-ultrasound-on-wound-repair-with-emphasis-on-fibroblast-activity(25c46b5a-7e78-45a4-a3ac-18a00881e8b9).html.
Full text
30
Brohlin, Maria. "Mesenchymal stem cells for repair of the peripheral and central nervous system." Doctoral thesis, Umeå universitet, Anatomi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-47746.
Full textAbstract:
Bone marrow-derived mesenchymal stem cells (MSC) have been shown to provide neuroprotection after transplantation into the injured nervous system. The present thesis investigates whether adult human and rat MSC differentiated along a Schwann cell lineage could increase their expression of neurotrophic factors and promote regeneration after transplantation into the injured peripheral nerve and spinal cord. Human and rat mesenchymal stem cells (hMSC and rMSC) expressed characteristic stem cell surface markers, mRNA transcripts for different neurotrophic factors and demonstrated multi-lineage differentiation potential. Following treatment with a cocktail of growth factors, the hMSC and rMSC expressed typical Schwann cells markers at both the transcriptional and translational level and significantly increased production of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). Age and time in culture are of relevance for clinical settings and growth-promoting effects of hMSC from young donors (16-18 years) and old donors (67-75 years) were compared. Undifferentiated hMSC from both young and old donors increased total neurite length of cultured dorsal root ganglion (DRG) neurons. Differentiation of hMSC from the young donors, but not the eldery donors, further enhanced the neurite outgrowth. Undifferentiated hMSC were cultured for eleven weeks in order to examine the effect of in vitro expansion time on neurite outgrowth. hMSC from the young donors maintained their proliferation rate and their ability to enhance neurite outgrowth from DRG neurons. Using a sciatic nerve injury model, a 10mm gap was bridged with either an empty tubular fibrin glue conduit, or conduits containing hMSC, with and without cyclosporine treatment. Cells were labeled with PKH26 prior to transplantation. At 3 weeks after injury the conduits with cells and immunosuppression increased regeneration compared with an empty conduit. PKH26 labeled human cells survived in the rat model and the inflammatory reaction could be suppressed by cyclosporine. After cervical C4 hemisection, BrdU/GFP-labeled rMSC were injected into the lateral funiculus rostral and caudal to the spinal cord lesion site. Spinal cords were analyzed 2-8 weeks after transplantation. Transplanted MSC remained at the injection sites and in the trauma zone for several weeks and were often associated with numerous neurofilament-positive axons. Transplanted rMSC induced up-regulation of vascular endothelial growth factor in spinal cord tissue rostral to the injury site, but did not affect expression of brain-derived neurotrophic factor. Although rMSC provided neuroprotection for rubrospinal neurons and significantly attenuated astroglial and microglial reaction, cell transplantation caused aberrant sprouting of calcitonin gene-related peptide immunostained sensory axons in the dorsal horn. In summary these results demonstrate that both rat and human MSC can be differentiated towards the glial cell lineage, and show functional characteristics similar to Schwann cells. hMSC from the young donors represent a more favorable source for neurotransplantation since they maintain proliferation rate and preserve their growth-promoting effects in long-term cultures. The data also suggest that differentiated MSC increase expression of neurotrophic factors and support regeneration after peripheral nerve and spinal cord injury.
31
Mullins, Fraser Hewitt. "Post-translational processing of microtubule protein during peripheral nerve regeneration." Thesis, University of Liverpool, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385223.
Full text
32
Villalta, Sergio Armando. "M1 and M2 macrophages promote muscle injury and repair during muscular dystrophy." Diss., Restricted to subscribing institutions, 2009. http://proquest.umi.com/pqdweb?did=2015941901&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
Full text
33
Newsome, Philip N. "Studies on cellular engraftment and hepatocytic differentiation in liver injury and repair." Thesis, University of Edinburgh, 2004. http://hdl.handle.net/1842/27118.
Full textAbstract:
Aim: In this thesis the factors which regulate the adhesion and survival of hepatocytes in the face of acute liver injury environment are examined. Also factors which regulate the differentiation of human stem cells towards hepatocytes are examined in vitro and in vivo. Materials and Methods: Human hepatoblastoma (HepG2) cells were used as a model of human hepatocytes to study the effect of serum from patients with acute liver failure. Various laboratory assays were used to determine effects on adhesion, cell necrosis/apoptosis, integrin expression (flow cytometry) and integrin activation. Human cord blood was used as a source of human stem cells for both in vitro experiments and the in vivo work with the NOD-SCID mice. Results: Paracetamol-induced liver injury results in the marked up regulation of collagen IV on hepatic sinusoids. Adhesion of HepG2 cells to Collagen IV after exposure to fulminant serum was reduced within only a few hours. Apoptosis occurred approximately 24-48 hours after incubation and is associated with caspase3 activation. Furthermore, fulminant serum reduces the adhesive capabilities of HepG2 cells by a rapid down-regulation of their β1-integrin activity. Loss of cellular adhesion and subsequent apoptosis can be reversed by treatment of HepG2 cells with the stimulatory mAb TS2/16. Human cord blood could not be directed in vitro down the hepatocytic lineage under any of the different combinations of cytokines/matrix. In vivo however infused human cord blood cells are capable of engrafting into NOD-SCID mouse liver and differentiating down the hepatocytic lineage without fusion to host hepatocytes. Conclusion: In this thesis mechanisms regulating the engraftment and survival of HepG2 cells during exposure to fulminant serum were identified. Human stem cells were also demonstrated in vivo (but not in vitro) to differentiate into hepatocytes within the NOD-SCID mouse liver with no evidence of cellular fusion.
34
Amer, Rebecca K. "Hepoxilins and neuronal repair, effects on SCG neurons after in vitro injury." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0021/MQ54161.pdf.
Full text
35
Mulay, Shrikant Ramesh. "Role of murine double minute (MDM)-2 in kidney injury and repair." Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-157682.
Full textAbstract:
Murine double minute (MDM)-2, an E3 ubiquitin ligase, promotes cancer cell survival and growth, by degrading the cell cycle regulator p53. Antagonism of MDM2 by the small-molecule cis-imidazoline nutlin analogs is currently under study for cancer therapy. We observed that MDM2 is strongly expressed by the epithelial cells in the kidney for example, tubular epithelial cells and podocytes. To test whether MDM2 promotes regenerative cell growth, we studied the effects of MDM2 antagonist, nutlin-3a on tubule cell healing during postischemic acute kidney injury and on podocytes during adriamycin induced chronic renal failure.
Consistent with the hypothesis, we observed that treatment with nutlin-3a impaired tubular cell regeneration during postischemic AKI in C57Bl6 wild-type mice in a p53-dependent manner. However, MDM2 blockade also prevented tubular necrosis by suppressing sterile inflammation during the early postischemic phase. This effect also occurred in p53-deficient mice, indicating a second, pro-inflammatory, p53-independent role for MDM2 in AKI. In-vitro experiments confirmed that MDM2 is required to induce mRNA expression and secretion of NF-κB-dependent cytokines upon Toll-like receptor stimulation by enhanced binding of NF-κB to cytokine promoter–binding sites. Thus, MDM2 links inflammation and epithelial healing during AKI. It promotes the inflammatory response after the injury at the same time it drives the regeneration of injured tubular epithelium. Therefore, these additional biological functions need to be regarded when considering MDM2 inhibition therapy in patients with acute renal failure.
Since, podocytes strongly express MDM2, we hypothesized that blocking MDM2 during glomerular injury may enhance podocyte apoptosis, proteinuria and glomerulosclerosis. However, unexpectedly MDM2 blockade in early adriamycin nephropathy in Balb/c mice had the opposite effect and reduced intrarenal cytokine and chemokine expression, glomerular macrophage and T cell counts, plasma creatinine and BUN levels. In cultured podocytes exposed to adriamycin, MDM2 blockade did not enhance podocyte apoptosis but rather prevented aberrant nuclear divisions and death of aneuploid podocytes, i.e. mitotic catastrophe. Accordingly, MDM2 blockade induced p21 and prevented podocyte mitosis in-vivo while TUNEL+ apoptotic podocytes were not detected. Thus, mitotic catastrophe is a previously unrecognized variant of podocyte loss where MDM2 promotes podocytes to complete the cell cycle, which in the absence of cytokinesis, leads to podocyte aneuploidy and death. Furthermore, delayed MDM2 blockade also reduced plasma creatinine levels, BUN, tubular atrophy, interstitial leukocyte numbers and cytokine expression as well as interstitial fibrosis. Together, MDM2 blockade with nutlin-3a could be a novel therapeutic strategy to prevent renal inflammation, podocyte loss, glomerulosclerosis, proteinuria, and progressive kidney disease.
In conclusion, therapeutic MDM2 blockade may hold the risk of impaired epithelial healing in AKI. On the other hand it may delay or halt the progression of glomerular disorders to CKD by reducing renal inflammation and by directly protecting podocytes from cell death by mitotic catastrophe.
36
Douglas, Samantha. "Potential roles for VEGF and TGF-[beta] in lung injury and repair." Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.535189.
Full text
37
Migliorini, Adriana. "Role of interferon-α and interferon-β in glomerular injury and repair." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-168014.
Full textAbstract:
Obwohl die immunstimulatorischen Effekte viraler Nukleinsäursen, wie auch IFN -α und IFN-β, während Virusinfektionen eine wichtige Rolle spielen, ist wenig über ihre Funktion bei viraler Glomerulonephritis, wie beispielsweise HIV Nephropathie, bekannt. Virusinfektionen aktivieren, vor allem mittels IFN-α und IFN-β Produktion eine systemische antivirale Immunantwort. Es wurde gezeigt, dass diese inflammatorischen Zytokine einen pleiotropen immunmodulatorischen Effekt auf renale Mesangialzellen ausüben, was direkt zu glomerulären Krankheiten führt. Aber es ist bisher nicht bekannt, ob die viralen Nukleinsäuren und Typ I IFN einen Effekt auf die glomerulären Epithelzellen haben. (z.B. Podozyten und PECs). Um den Effekt von Nukleinsäuren auf Podozyten und PECs zu erforschen, stimulierten wir diese Zellen mit synthetischen dsDNA-(poly-dAdT) Komplexen mit lipofectamine, um eine virale Infektion zu imitieren. Wir haben herausgefunden, dass dsDNA stetig viele IFN-stimulierte Gene in Podozyten und PECs induziert. Desweitern haben wir herausgefunden, dass dsDNA die PECs Proliferation mindert und die CD24+/CD133+PECs Differenzierung zu ausgereiften Podozyten inhibiert. Um unsere Hypothese, dass deis aufgrund von der Sekretion von IFN-α und IFN-β passiert ist, zu bestätigen, haben wir den Effekt von diesen anitviralen Zytokinen auf PECs- und Podozyten-Homöostase etabliert. Wir haben herausgefunden, dass beide IFNs stetig Podozyten und PECs dazu anregen, stetig mehrere IFN-stimulierte Gene zu exprimieren. Trotzdem hat nur IFN-β das Podozytensterben induziert und die Permeabilität der Podozyten-Monolayer erhöht.
In der Adriamycin-induzierter Nephropathie bei SCID Mäusen haben Injektionen mit IFN-α oder IFN-β die Proteinurie, den Makrophagen Influx und die Glomerulosklerose verstärkt. Trotzdem induziert nur IFN-β das mitotische Podozytensterben (katastrophale Mitose), welches zu einer reduzierten Podozytenanzahl führt. Wir haben führt, dass IFN-α einen Zellzyklusarrest in-vivo bei PECs induziert, der zur glomerulären Schädigung führt. Balb/c Mäuse, die Adriamycin gespritzt bekommen haben und täglich mit IFN-α und IFN-β behandelt wurden zeigten einen aggravierten Phänotyp mit vermehrter Proteinurie. Im Gegensatz zu dem, was an Studien in SCID Mausen gezeigt wurde, war der Effekt auf die Proteinurie nach IFN-α Behandlung prominenter bei Balb/c Mäusen, verglichen mit IFN-β. Deshalb haben Typ I IFNs einen deutlichen Effekt auf Podozyten und Parietalzellen. Zusammen fördern die Typ I IFNs die Glomerulosklerose durch verstärkten Untergang der Podozyten sowie durch Unterdrückung ihrer Regeneration aus Vorläuferzellen.
38
Jerosch-Herold, Christina. "The clinical assessment of hand sensibility after peripheral nerve injury and repair." Thesis, University of East Anglia, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246673.
Full text
39
Mitchell, Andrew Joseph. "Understanding the role of endothelial progenitor cells in vascular injury and repair." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33310.
Full textAbstract:
Introduction: Vascular injury is the crucial initiating event in atherosclerosis and is universal following percutaneous coronary intervention. The cellular response to this injury largely determines vessel outcome. Endothelial progenitor cells (EPCs) and their progeny, late outgrowth endothelial cells (EOCs) are thought to play an important role in this process and characterising this role would be valuable in better understanding vascular injury and repair. Methods: The radial artery in the context of transradial cardiac catheterisation was examined as a model of vascular injury with characterisation of structural injury, longitudinal function and EPC populations. To examine the role of late outgrowth endothelial cells a method for GMP-compliant cell culture and labelling with F18Fluorodeoxyglucose was developed with a view to conducting a cell-tracking study of human administration. Results: Radial artery function was reduced following transradial cardiac catheterisation with recovery over a period of three months. There was no correlation between recovery of arterial function and EPC populations as defined by conventional surface markers. A research grade protocol for EOC culture was successfully translated to a GMP-compliant process producing a viable, phenotypically homogeneous EOC product. Cells were successfully labelled with F18Fluorodeoxyglucose and whilst proliferation was reduced, acute viability and function were not compromised. Conclusion: The radial artery in the context of transradial cardiac catheterisation is a useful model of vascular injury and repair although recovery of vascular function does not appear to be influenced by EPC populations. GMP-compliant culture and labelling of EOCs is feasible and will allow examination of the physiology of these cells in vivo in man.
40
Hesp, Zoe Ciambro. "The Role of NG2+ Cells in Endogenous Repair after Spinal Cord Injury." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487785833325771.
Full text
41
Sen, Moen. "p16 Regulation of Lung Epithelial Cell Growth, Repair after Injury and Transformation." University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504873926115934.
Full text
42
Paleo, Brian J. "Demonstrating The Importance Of Membrane Repair In Response To Disease And Injury." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1595504131615976.
Full text
43
Whitehead, Michael. "The role of heparan sulphates in peripheral nerve injury, repair and myelination." Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/9128/.
Full textAbstract:
Peripheral neuropathies (PN) represent a significant health burden, due to chronic and debilitating symptoms, that can be inherited or caused by everything from alcohol,chemotherapy and diabetes. PN are associated with both demyelination and axon degeneration, which play a fundamental role in their pathogenesis. The aim of this thesis is to identify novel mechanisms and/or potential therapeutics for protecting axon degeneration and promoting myelination. This is significant because there are currently no specific therapeutics, for PN, that have passed clinical trial successfully. Recent work in the Barnett lab has implicated heparan sulphate proteoglycans (HSPGs), as therapeutic targets in central nervous system (CNS) injury. HSPGs are able to bind a plethora of proteins, including chemokines and growth factors, where they facilitate binding to their corresponding receptors. We therefore hypothesised that HSPGs may have a regulatory role in PNS injury. To address this I data mined previously published microarrays for sciatic nerve (SN) injury. This principally identified the candidate heparanase (Hpse),which was up-regulated after injury in several different microarray analyses. Hpse is able to regulate HSPG signalling and is already implicated in several diseases including: cancer, diabetes and Alzheimer’s disease, making it an interesting candidate for further research. In order to question the role of Hpse in PNS injury we used two models of Wallerian degeneration:ex vivo SN injury model and an ex vivo neuromuscular junction (NMJ) injury model. Inhibiting Hpse acutely accelerated axon loss, while its exogenous treatment was protective. Furthermore we found that Hpse can regulate β-catenin protein levels and the transcription of genes, predicted to be regulated by β-catenin. This included Sox2, which led to an acceleration in Schwann cell dedifferentiation after in-jury. Recent evidence has linked Schwann cell dedifferentiation to early events in axon fragmentation. We also found that heparin sulphate mimetics significantly promote in vitro myelination, the mechanism for which requires further research. In conclusion, we have identified Hpse, an up-regulated enzyme after SN injury, in protecting axon loss during SN degeneration. Within the field, Wallerian degeneration is considered a useful model for studying the mechanisms behind axon loss in peripheral neuropathies, for which the role of Hpse warrants further investigation as a potential therapeutic target. Lastly we also identified heparin sulphate mimetics in promoting peripheral myelination, also making them potential therapeutic targets.
44
Ojha, Navdeep. "Imaging of tissue injury-repair addressing the significance of oxygen and its derivatives." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1196204993.
Full text
45
McKechnie, Stuart R. "The roles of hyperoxia and mechanical deformation in alveolar epithelial injury and repair." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/2691.
Full textAbstract:
The alveolar epithelium is a key functional component of the air-blood barrier in the lung. Comprised of two morphologically distinct cell types, alveolar epithelial type I (ATI) and type II (ATII) cells, effective repair of the alveolar epithelial barrier following injury appears to be an important determinant of clinical outcome. The prevailing view suggests this repair is achieved by the proliferation of ATII cells and the transdifferentiation of ATII cells into ATI cells. Supplemental oxygen and mechanical ventilation are key therapeutic interventions in the supportive treatment of respiratory failure following lung injury, but the effects of hyperoxia and mechanical deformation in the injured lung, and on alveolar epithelial repair in particular, are largely unknown. The clinical impression however, is that poor outcome is associated with exposure of injured (repairing) epithelium to such iatrogenic ‘hits’. This thesis describes studies investigating the hypothesis that hyperoxia & mechanical deformation inhibit normal epithelial repair. The in vitro data presented demonstrate that hyperoxia reversibly inhibits the transdifferentiation of ATII-like cells into ATI-like cells with time in culture. Whilst confirming that hyperoxia is injurious to alveolar epithelial cells, these data further suggest the ATII cell population harbours a subpopulation of cells resistant to hyperoxia-induced injury. This subpopulation of cells appears to generate fewer reactive oxygen species and express lower levels of the zonula adherens protein E-cadherin. Using a panel of antibodies to ATI (RTI40) and ATII (MMC4 & RTII70) cell-selective proteins, the effect of hyperoxia on the phenotype of the alveolar epithelium in a rat model of resolving S. aureus-induced lung injury was investigated. These in vivo studies support the view that, under normoxic conditions, alveolar epithelial repair occurs through ATII cell proliferation & transdifferentiation of ATII cells into ATI cells, with transdifferentiation occurring via a novel intermediate (MMC4/RTI40-coexpressing) immunophenotype. However, in S. aureus-injured lungs exposed to hyperoxia, the resolution of ATII cell hyperplasia was impaired, with an increase in ATII cell-staining membrane and a reduction in intermediate cell-staining membrane compared to injured lungs exposed to normoxia alone. As hyperoxia is pro-apoptotic and known to inhibit ATII cell proliferation, these data support the hypothesis that hyperoxia impairs normal epithelial repair by inhibiting the transdifferentiation of ATII cells into ATI cells in vivo. The effect of mechanical deformation on alveolar epithelial cells in culture was investigated by examining changes in cell viability following exposure of epithelial cell monolayers to quantified levels of cyclic equibiaxial mechanical strain. In the central region of monolayers, deformation-induced injury was a non-linear function of deformation magnitude, with significant injury occurring only following exposure to strains greater than those associated with inflation of the intact lung to total lung capacity. However, these studies demonstrate for the first time that different epithelial cell phenotypes within the same culture system have different sensitivities to deformation-induced injury, with spreading RTI40-expressing cells in the peripheral region of epithelial cell monolayers and in the region of ‘repairing’ wounds being injured even at physiological levels of mechanical strain. These findings are consistent with the hypothesis that alveolar epithelial cells in regions of epithelial repair are highly susceptible to deformation-induced injury.
46
Tomecka, Monika Jagoda. "Crush injury in zebrafish tail as a model for human bone fracture repair." Thesis, University of Sheffield, 2016. http://etheses.whiterose.ac.uk/16458/.
Full text
47
Yang, Ziquan. "Repair of cartilage injury using gene modified stem cells and acellular cartilage matrix." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501585.
Full text
48
Horn, Kevin Paul. "An Investigation of the Role of Macrophages in Spinal Cord Injury and Repair." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1249267954.
Full text
49
Weightman, Alan Peter. "Enhancing the complexity of neural tissue engineering platforms for repair of neurological injury." Thesis, Keele University, 2015. http://eprints.keele.ac.uk/1205/.
Full textAbstract:
The extent of regeneration is often limited after spinal cord injury (SCI), due to the post-injury microenvironment that is unsupportive of nerve fibre regeneration and the limited intrinsic reparative capacity of neurons. Current mainstream clinical therapies focus on reducing the extent of damage in the early stages of injury, rather than promoting regenerative mechanisms in sites of pathology. In this context, one promising biomedical engineering strategy emerging globally to promote repair following SCI is the reconstruction of neural circuitry in injury sites via the implantation of polymer scaffolds, or ‘structural bridges.’ To date, the development of such synthetic bridges has faced two major challenges: an overwhelming reliance on basic 2-D scaffolds functionalised with single cell types (which therefore fail to mimic the complex circuitry of the neural lesion environment); and heavy dependence on live animal models of neurological injury for functional screening and developmental testing, in the absence of in vitro injury models that mimic the complex pathological sequelae of neurological injury in vivo. To this end, this thesis demonstrates an enhancement of the spatial and cellular complexity of both nanofibre-based scaffolds for spinal cord repair and in vitro SCI models for screening efficacious scaffold formulations. Nanofibre-hydrogel constructs containing aligned glial cell co-cultures (derived from primary sources) were successfully developed by systematically optimising the assembly protocol and construct design features. Further, protocols were developed to demonstrate the feasibility of increasing the number of constituent nanofibre layers in constructs with astrocyte mono-cultures, for further processing of constructs into an implantable form. A safe and effective method of inducing complete transecting lesions in organotypic spinal cord slice cultures was developed following the production of a prototype double-bladed lesioning tool. The development of quantitative image-based assays of fluorescently labelled astrocyte, microglial and neuronal cell populations within slice lesion sites showed mimicry of multiple cardinal features of neurological injury in vivo. Finally, a method was developed to coat portable frames of aligned nanofibres with therapeutic biomolecules and incorporate frames into lesioned slices. Patterns of nanotopography induced outgrowth/alignment of astrocytes and neurons in the in vitro model were strikingly similar to that induced by comparable materials in related studies in vivo. This demonstrates the predictive utility of the model and the potential to reduce and refine the use of lower-throughput live animal models for screening applications.
50
Seol, Dong Rim. "Chondrogenic progenitor cell response to cartilage injury and its application for cartilage repair." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/1262.
Full textAbstract:
Focal damage to cartilage sustained in serious joint injuries typically goes unrepaired and may progress to post-traumatic osteoarthritis. However, in a bovine explant model we found that cartilage damage provoked the emergence of highly migratory cells that homed to the site of injury and appeared to re-populate dead zones. We hypothesized that the migrating population were chondrogenic progenitor cells engaged in cartilage repair. The surfaces of bovine osteochondral explants injured by blunt impact were serially imaged to follow cell migration. Migrating cells harvested from cartilage surfaces were tested for clonogenic, side population, chemotactic activities and multipotency in in vitro assays. Gene expression in migrating cells was evaluated by microarray and their potential for spontaneous cartilage regeneration was assessed in a chondral defect model. Migrating cells emerged from superficial zone cartilage and efficiently repopulated areas where chondrocyte death had occurred. In confocal examination with high magnification, we could clearly observe the morphology of elongated progenitor cells which were migrating toward cartilage defect area and these cells were distinguishable from round chondrocytes. The cells were also activated to migrate in cartilage defect model. Most migrated cells in fibrin were morphologically elongated and a few cells were differentiating to chondrocyte-like cells with the deposit of proteoglycans. These cells proved to be highly clonogenic and capable of chondrogenesis and osteogenesis, but not adipogenesis. They were more active in chemotaxis assays than chondrocytes, showed a significantly larger side population, and over-expressed progenitor cell markers and genes involved in migration, chemotaxis, and proliferation. To active migration of chondrogenic progenitor cells (CPCs) short-term enzymatic method was used around edge of cartilage defect. Surprisingly, CPCs migrated into fibrin defect and were differentiating into chondrocytes with abundant deposit of proteoglycans. This result strongly supports that progenitor cells are activated in traumatic cartilage injury and have great potential for cartilage repair. In conclusion, migrating cells on injured explant surfaces are chondrogenic progenitors from the superficial zone that were activated by cartilage damage to attempt repair. Facilitating this endogenous process could allow repair of focal defects that would otherwise progress to post-traumatic osteoarthritis.