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Artykuły w czasopismach na temat "DS rodent models"
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Zhang, Tan, Xin Wang, Hannah M. Jester, Xueyan Zhou i Tao Ma. "Characterization of Apathy-Like Behaviors in Mouse Models of Down Syndrome". Journal of Alzheimer's Disease 101, nr 4 (8.10.2024): 1217–26. http://dx.doi.org/10.3233/jad-240675.
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Background: Apathy is a state of decreased interest, lack of initiative, reduced goal-directed activity and blunted emotional responses. Apathy is one of the most common neuropsychiatric symptoms (NPS) in patients with Alzheimer’s disease (AD) and is also relatively omnipresent in individuals with Down syndrome (DS). Little is known about the apathy-like behaviors in rodent models of AD and DS. Objective: This study aimed to characterize apathy-like behaviors with aging in two established DS mouse models: Ts65Dn and Dp16. Methods: A battery of behavioral tests including nestlet shredding, marble burying, nest building, and burrowing were performed to examine apathy-like behaviors. Individual z-scores for each mouse for each test, and a composite z-score of apathy-like behavior were analyzed for all mice from these behavioral tests. Results: Analysis of individual test results and composite z-score revealed significant apathy-like behaviors in Ts65Dn mice compared to WT controls. In contrast, Dp16 mice did not exhibit significant apathy-like behaviors. Conclusions: Our study is the first to characterize apathy-like behaviors in mouse models of DS with aging and highlights the difference between Ts65Dn and Dp16 DS model mice regarding apathy-like manifestations with aging.
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Bartesaghi, Renata, Stefano Vicari i William C. Mobley. "Prenatal and Postnatal Pharmacotherapy in Down Syndrome: The Search to Prevent or Ameliorate Neurodevelopmental and Neurodegenerative Disorders". Annual Review of Pharmacology and Toxicology 62, nr 1 (6.01.2022): 211–33. http://dx.doi.org/10.1146/annurev-pharmtox-041521-103641.
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Those with Down syndrome (DS)—trisomy for chromosome 21—are routinely impacted by cognitive dysfunction and behavioral challenges in children and adults and Alzheimer's disease in older adults. No proven treatments specifically address these cognitive or behavioral changes. However, advances in the establishment of rodent models and human cell models promise to support development of such treatments. A research agenda that emphasizes the identification of overexpressed genes that contribute demonstrably to abnormalities in cognition and behavior in model systems constitutes a rational next step. Normalizing expression of such genes may usher in an era of successful treatments applicable across the life span for those with DS.
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Deckert, Jutta, Jenny Thirlway, Yun-Hee Park, Ho Young Song, Chul-Woong Chung, Xuesong Wang, Zhenshan Zhang i Robert J. Lutz. "Abstract 1753: IKS014, a HER2-targeting antibody drug conjugate incorporating novel bioconjugation and tumor-selective linker technology with improved in vivo efficacy and tolerability". Cancer Research 82, nr 12_Supplement (15.06.2022): 1753. http://dx.doi.org/10.1158/1538-7445.am2022-1753.
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Abstract HER2 has long been a target of high interest for antibody and antibody drug conjugate (ADC) therapeutics due to its well-documented overexpression in breast, gastric and lung cancer. While trastuzumab and ado-trastuzumab emtansine (T-DM1) have become an integral part of treatment paradigms for HER2-positive cancer, the more recent approvals of the fam-trastuzumab deruxtecan (DS-8201) ADC and the Fc-engineered margetuximab antibody have highlighted the potential for continued improvement over existing HER2-targeting therapies. IKS014 is a HER2-directed ADC that incorporates site-directed conjugation and tumor-selective glucuronide-trigger linker technology to reduce systemic off-target toxicity while maximizing efficient intracellular lysosomal payload release, thus holding the promise of a wider therapeutic index. IKS014 was generated by site-specific conjugation via a proprietary beta-glucuronide linker to the microtubule agent MMAF with a drug-to-antibody ratio (DAR) 2. In vitro and in vivo activity was evaluated in HER2-positive preclinical models with varying HER2 expression levels in comparison to benchmark ADCs. Pharmacokinetics (PK) and tolerability studies were conducted in rodent and cynomolgus monkey. IKS014 conjugation resulted in a homogeneous ADC with defined DAR and good physio-chemical properties. In vitro, IKS014 demonstrated dose dependent specific cytotoxicity against Her2-positive cell lines. In JIMT-1 breast cancer xenografts with moderate HER2-expression (HER2 IHC 2+), IKS014 causes complete regressions at a single dose of 5 mg/kg and partial regressions at 1 mg/kg, while T-DM1 results in only tumor growth inhibition even at 15 mg/kg. Anti-tumor efficacy of IKS014 in NCI-N87 (HER2 3+) gastric xenografts is comparable to DS-8201 but superior to T-DM1 at equivalent single doses ranging from 1 to 5 mg/kg. In a HER2-positive patient-derived gastric cancer model (HER2 2+), IKS014 was highly active at 5mg/kg Q2W x2, while T-DM1 was inactive at the same dosing schedule. IKS014 demonstrated stable PK with a terminal half-life of 8.7 days in rat and 4.6 days in monkey, and DAR 2 was maintained for up to 4 weeks. In cynomolgus monkeys, IKS014 was tolerated at 12 mg/kg single dose and 5 mg/kg repeat dose without ocular or lung toxicity findings. IKS014 was highly efficacious against HER2-positive tumor xenografts in vivo, including models with moderate target expression, and compared favorably to clinically validated benchmark ADCs. This improved preclinical efficacy combined with stable PK and good tolerability profile warrants further development of this novel ADC for HER2-positive cancers. Citation Format: Jutta Deckert, Jenny Thirlway, Yun-Hee Park, Ho Young Song, Chul-Woong Chung, Xuesong Wang, Zhenshan Zhang, Robert J. Lutz. IKS014, a HER2-targeting antibody drug conjugate incorporating novel bioconjugation and tumor-selective linker technology with improved in vivo efficacy and tolerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1753.
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Zhang, Xichen, Michael W. Epperly, Mark A. Kay, Zhi-Ying Chen, Tracy Smith, Darcy Franicola, Benjamin Greenberger, Paavani Komanduri i Joel S. Greenberger. "Minicircle Plasmid Containing the Human Manganese Superoxide Dismutase (MnSOD) Transgene Confers Radioprotection to Hematopoietic Progenitor Cell Line 32Dcl3." Blood 110, nr 11 (16.11.2007): 5138. http://dx.doi.org/10.1182/blood.v110.11.5138.5138.
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Abstract Manganese superoxide dismutase plasmid/liposomes (MnSOD-PL) delivered by intratracheal, intraesophageal, or intraoral routes in rodent models has been demonstrated to confer organ specific ionizing irradiation protection. In addition intravenous injections of MnSOD-PL protect mice from whole body irradiation. Currently a seven week phase I/II clinical trial is in progress in lung cancer patients consisting of twice weekly swallowed MnSOD-PL for protection of the esophagus from chemoradiotherapy damage. To prepare for a potential clinical trial of systemic MnSOD-PL for radioprotection in humans, plasmid bacterial sequences were removed to diminish the immune response. The human MnSOD transgene attached to a CMV promoter and a poly A tail was inserted in the site between Spe I and Xho I into a eukaryotic expression cassette located in the p2ØC31 plasmid. The plasmid contains an endonuclease I-SceI gene which can be cleaved resulting in the formation of two minicircle plasmids. The smaller minicircle contains the eukaryotic expression cassette but no bacterial sequences while the larger minicircle plasmid contains the plasmid bacterial backbone. The minicircle MnSOD was purified and then co-transfected into 32Dcl3 murine hematopoietic progenitor cells with a plasmid containing the neo gene. Cells were selected in G418 (50μg/ml G418) and cloned by limiting dilution into 96 well plates. The clones were expanded and analyzed by PCR for the presence of the human MnSOD transgene using primers specific for the human MnSOD. One clone was chosen and the MnSOD biochemical activity was determined. The 32Dcl3 cells had a specific MnSOD activity of 2.7 ± 0.1 U/mg protein compared to 5.8 ± 0.5 U/mg protein for the 32D-mc-MnSOD clone (p=0.0039). To determine if the MnSOD transgene in the minicircle DNA retained radioprotective capacity 32D-mc-MnSOD, a clone transfected with a pRK5 plasmid containing the human MnSOD transgene (2C6), and parent 32Dcl3 cells were irradiated to doses of 0–8 Gy then grown at 37° C for 7 days at which time colonies of greater than 50 cells were counted. The data was analyzed by linear quadratic and single-hit, multi-target models. The 32D-mc-MnSOD cells were more radioresistant than 32Dcl3 cells as demonstrated by an increased shoulder on the irradiation survival curve (n = 4.8 ± 0.2 compared to 1.5 ± 0.5, respectively, p = 0.0078). In contrast, there was no significant reduction in the shoulder of the survival curve comparing 32D-mc-MnSOD and 2C6 (n = 4.8 ± 0.2 and 4.6 ± 0.2, respectively). In vivo C57BL/6NHsd mice received intraoral mc-MnSOD-PL, mc-DS-red-PL, MnSOD-PL or Blank-PL, swallowed the plasmid/liposome complexes and were then irradiated 24 hr later along with control mice to 31 Gy to the esophagus. Mice receiving mc-MnSOD-PL had increased survival compared to both the control mice or mice treated with mc-DS-red-PL (p = 0.0099 or 0.0391, respectively). There was significant and equivalent improved survival of mice injected with mc-MnSOD-PL compared to full length MnSOD-PL. Therefore minicircle DNA containing the human MnSOD transgene confers undiminished radioprotection to cells in vitro and the esophagus in vivo compared to a fully intact plasmid containing the MnSOD transgene.
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Jin, Shanshan, Xiaochen Zhang, Yunlu Jia, Yongchao Dai, Fengwei Xu, Yongfeng Huang, Xun Wang i in. "The design, preclinical study and phase I dose escalation plan of a HER2 targeted immunoliposome (HF-K1) for HER2 low solid tumor treatment." Journal of Clinical Oncology 42, nr 16_suppl (1.06.2024): 3035. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.3035.
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3035 Background: Doxorubicin liposome formulations are being used extensively in the clinic in anthracycline chemotherapy with reduced cardiotoxicity. However, they did not improve clinical outcome because the cancer cell uptake of PEG-coated liposomes is poor. So, the concept of coating antibodies on the liposome surface was initiated and they were named immunoliposomes. There have been numerous studies conducted world-wide for the development of immunoliposomes but none have progressed to late-stage development. Our work draws on the experiences of these prior studies with a new perspective. Since the mechanism of immunoliposomes is similar to those of ADCs, we sought to compare immunoliposomes with ADCs containing the same cancer cell binding domain, for target cell binding capability, binding affinity as well as in vivo distribution, tumor tissue accumulation, and anti-tumor activities. The lessons learned from the success of many ADC products may be applicable to the development of immunoliposomes. Methods: The antibody to liposome ratio (ALR) and the drug to lipid ratio (DLR) of the immunoliposomes were selected by in vitro and in vivo anti-cancer activity screening. Cell lines with different HER2 expression levels were used to study immunoliposome binding, cell uptake, drug delivery and cytotoxicity. PK, drug distribution, efficacy and toxicities studies were conducted in respective CDX and PDX mice and non-rodent models. Based on these studies, a phase I dose escalation study plan was designed and the study is now ongoing. Results: HF-K1 was designed to have an average of 10 anti-HER2 Fab on each liposome surface and approximately 2300 doxorubicin molecules inside. The equivalent drug to antibody ratio (DAR) is 230. HF-K1 can bind to cancer cells with different levels of HER2 expression with similar kinetics and induces cells death at IC50s of 0.35-6.46 μg/ml Fab concentration. It has a long circulation behavior and enhanced permeability and retention (EPR) in tumor tissues. The clearance T1/2 of HF-K1 in mice and monkey is 12.78 h and 47.12 h, respectively. Evaluation of HF-K1 activity in vivo showed significant tumor growth inhibition >95% at the equivalent antibody dose of 3.6 mg/kg in various mouse tumor models including HER2 low and HER2 very low (HER2-). Similar activities were shown by ADCs including T-DM1 and DS-8201a at about 10 mg/kg. Conclusions: The encouraging preclinical data supported a clinical trial starting with dose escalation at equivalent antibody doses of 0.72 mg/m2, 2.16 mg/m2, 5.4 mg/m2, 10.8 mg/m2, 16.2 mg/m2, and 21.6 mg/m2. The study is ongoing to determine the safety, tolerability, PK, and preliminary antitumor efficacy in participants with HER2 positive or HER2 low expression advanced solid tumors (NCT05861895). Clinical trial information: NCT05861895 .
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Nonoguchi, Hannah A., Timothy Wee Shang Kouo, Sandhya Kortagere, Joshua Hillman, David L. Boyle i Chitra D. Mandyam. "Lipopolysaccharide Exposure Differentially Alters Plasma and Brain Inflammatory Markers in Adult Male and Female Rats". Brain Sciences 12, nr 8 (24.07.2022): 972. http://dx.doi.org/10.3390/brainsci12080972.
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Humans and rodents have sexually dimorphic immune responses, which could influence the brain’s response to a systemic inflammatory insult. Lipopolysaccharide (LPS) is a stimulator of the innate immune system and is routinely used in animal models to study blood–brain barrier (BBB) dysfunction under inflammatory conditions. Therefore, we examined whether inflammatory response to LPS and the associated BBB disruption differed in male and female adult rats. Rats were treated with saline or two injections of 1 mg/kg LPS and studied 24 h after the second LPS injection. Plasma isolated from trunk blood and brain tissue homogenates of the prefrontal cortex (PFC), dorsal striatum (DS), hippocampus, and cerebellum were analyzed for cytokines and chemokines using a 9-plex panel from Meso Scale Discovery. BBB disruption was analyzed with tight junction proteins claudin-5 and VE-cadherin via Western blotting and VEGF by ELISA. This allowed us to compare sex differences in the levels of individual cytokines as well as associations among cytokines and expression of tight junction proteins between the plasma and specific brain regions. Higher levels of interferon-γ, interleukin-10 (IL-10), IL-13, IL-4, CXCL-1, and VEGF in the plasma were revealed compared to the brain homogenates, and higher levels of TNFα, IL-1β, IL-6, and IL-5 in the PFC were seen compared with plasma and other brain regions in males. Females showed higher levels of plasma CXCL1 and VEGF compared to males, and males showed higher levels of PFC TNFα, IL-6, IL-4, and VEGF compared to females. LPS induced significant increases in plasma cytokines and VEGF in both sexes. LPS did not significantly alter cytokines in brain tissue homogenates, however, it increased chemokines in the PFC, DS, and hippocampus. In the PFC, LPS produced BBB disruption, which is evident as reduced expression of claudin-5 in males and reduced expression of VE-cadherin in both sexes. Taken together, our results reveal significant sex differences in pro-inflammatory cytokine and chemokine levels in plasma and brain that were associated with BBB disruption after LPS, and validate the use of multiplex assay for plasma and brain tissue samples.
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Venkateshappa, Chandregowda, Kishore Narayanan, Rashmi Nair, Aravind AB, Ramakishore VP Putta, Jwala Nagaraj, Megha Goyal i in. "Abstract 4432: A highly differentiated A2AR inhibitor for potential use in cancer therapy". Cancer Research 83, nr 7_Supplement (4.04.2023): 4432. http://dx.doi.org/10.1158/1538-7445.am2023-4432.
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Abstract As a potent immunosuppressor adenosine is essential for maintaining tissue homeostasis and preventing an overzealous immune response during inflammation and infection. However, adenosine generated within the tumor microenvironment by the action of ectonucleotides hinders the immune reaction towards cancer cells by signaling through adenosine receptors such as high affinity A2AR expressed on immune cells. Tumors evade the immune response by usurping pathways that negatively regulate normal immune responses. Resistance to inhibition of immune checkpoint targets arises because of an upregulation in the expression of the CD39-CD73 axis and the resulting increase in production of adenosine in the tumor microenvironment. Inhibition of either adenosine generation or signaling by inhibition of A2AR along with other immune activation strategies have been shown to be effective therapeutic approaches. In view of this, we sought to discover and develop novel small molecule inhibitors that dually target A2AR and an immuno-suppressive ligand expressed in the tumor microenvironment. Aurigene’s dual inhibitors exhibit potent inhibition of both A2AR and an immuno-suppressive target of relevance in respective biochemical assays. Potent biochemical activity translated into rescue of chemokines and IL-2 in human PBMCs. Lead compounds exhibited desirable drug-like properties and excellent pharmacokinetic exposure in rodents. In a syngeneic tumor model, lead compounds demonstrated significant tumor growth inhibition. Anti-tumor efficacy correlated well with tumor drug levels and modulation of pharmacodynamic markers. In summary, we have identified first-in-class dual inhibitors with good drug like properties, which showed significant antitumor efficacy. Evaluation of these lead compounds in additional tumor models and in vivo toxicity studies will be presented. Citation Format: Chandregowda Venkateshappa, Kishore Narayanan, Rashmi Nair, Aravind AB, Ramakishore VP Putta, Jwala Nagaraj, Megha Goyal, Vijay Kamal Ahuja, Amith A Dhudashiya, Samiulla DS, Girish Daginakatte, Thomas Antony, Kavitha Nellore, Susanta Samajdar, Murali Ramachandra. A highly differentiated A2AR inhibitor for potential use in cancer therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4432.
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Khare, Leena, Ramulu Poddutoori, Subhendu Mukherjee, Samiulla DS, Devaraja TS, Sivapriya Marappan, Shilpa Nayak i in. "Abstract B172: Potent anti-tumor activity of a selective and orally bioavailable reversible covalent CDK12 inhibitor". Molecular Cancer Therapeutics 22, nr 12_Supplement (1.12.2023): B172. http://dx.doi.org/10.1158/1535-7163.targ-23-b172.
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Abstract Cyclin-dependent kinase 12 (CDK12), in association with Cyclin K (CycK), regulates the elongation of transcription by modifying RNA polymerase II (RNAP II) through phosphorylation at Serine 2 (pS2) in the C-terminal domain, CDK12 plays an important role in maintaining genomic stability by modulating crucial cellular processes such as DNA damage response, splicing, and pre-mRNA processing. Overexpression of CDK12 has been observed in various tumor types, suggesting its potential oncogenic properties like other kinases involved in transcription. Given its significance in transcription and RNA processing, CDK12 has emerged as a promising therapeutic target for cancer treatment. We have identified a highly potent and selective reversible covalent inhibitor of CDK12, AU-22880, which exhibits significant anti-proliferative activity across various cancer cell lines. The covalent mode of action and on-target activity of AU-22880 were confirmed in a CDK12 target engagement assay and selective pS2 RNAPII inhibition respectively in a cellular context. Additionally, it has shown synergistic activity in combination with several standard-of-care agents in breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer cell lines. AU-22880 shows desirable ADME-PK properties and demonstrates excellent anti-tumor activity in xenograft models. In the HCC-70 TNBC xenograft model, AU-22880 demonstrated anti-tumor efficacy at well-tolerated doses. A pharmacokinetic-pharmacodynamic (PK-PD) study revealed dose-dependent target engagement, as evidenced by the inhibition of pS2 RNAPII and DNA damage repair (DDR) genes. Furthermore, AU-22880 exhibited good tolerability in rodents, dog, and monkeys at exposure levels that demonstrated efficacy. Efficacy of AU-22880 in combination with approved SOCs targeting DDR pathway are currently being investigated. The findings reported here highlight the promising therapeutic potential of AU-22880, both as a monotherapy and in combination with existing treatments for the treatment of cancers characterized by DDR dysregulation. Citation Format: Leena Khare, Ramulu Poddutoori, Subhendu Mukherjee, Samiulla DS, Devaraja TS, Sivapriya Marappan, Shilpa Nayak, Sasirekha Sivakumar, Lakshmi Kaza, Suraj Tgore, Amit Dhudashiya, Raghavendra NR, Bhargav Gunnepalli, Aravind A B, Amith A, Charamanna KB, Thomas Antony, Kavitha Nellore, Girish Daginakatte, Shekar Chelur, Sanjeev Giri, Murali Ramachandra, Susanta Samajdar. Potent anti-tumor activity of a selective and orally bioavailable reversible covalent CDK12 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B172.
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Farrell, Clíona, Paige Mumford, Millie Beament, Gloria Lau, Yixing Wu, Marion Pellen, Monika Rataj Baniowska i in. "Modelling of the development and response to amyloid‐β accumulation in the context of trisomy21 in the rodent brain". Alzheimer's & Dementia 19, S12 (grudzień 2023). http://dx.doi.org/10.1002/alz.075677.
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AbstractBackgroundIndividuals who have Down syndrome (DS), a genetic condition caused by having three copies of chromosome 21, frequently develop early‐onset Alzheimer’s disease (AD). This is caused by the additional copy of the APP gene, located on chromosome 21, which leads to a raised abundance of amyloid‐β. However, significant evidence demonstrates that the additional copy of other genes on the chromosome modifies the accumulation and response to amyloid‐β. Here we present a series of rodent preclinical models of AD‐DS, which we use to investigate this biology and can be used to test potential therapeutic approaches.MethodsWe previously crossed mouse models of DS with the AppNL‐F model of amyloid‐β accumulation; demonstrating that three copies of a region of chromosome 21 containing 38 genes is sufficient to reduce the accumulation of amyloid‐β. Here we present new data from a cross of the Dp1Tyb DS mouse model with an App gene knock‐out (to normalise the number of copies of this gene) and novel DS‐AD rodent models in which the endogenous App gene has been partially humanized (Dup(Rno11)‐APP‐H3 and Ts68Yah) compared with DS model controls (Dup(Rno11) and Ts66Yah). Brain material from these models at a range of ages was analyzed by western blot, biochemical fractionation and MSD assay, and immunohistology to study APP processing and amyloid‐β accumulation. We used MSD assay and immunofluorescence to study the response to accumulating amyloid‐β with a focus on the response of microglia, neuroinflammation and break‐down of the blood‐brain barrier.ResultsOur data indicate that three copies of App contribute to altered microglia biology in the Dp1Tyb mouse model of DS and that partial humanization of the App gene in DS rodent models leads to alterations in the processing of APP, and results in raised levels of human amyloid‐β in the brain.ConclusionThese new model systems of DS‐AD amyloid‐β biology can be used to better understand the early development of AD in people who have DS and to test the safety and efficacy of new therapies for this important group of individuals who are at extremely high risk of developing early onset dementia.
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Farrell, Clíona, Paige Mumford i Frances K. Wiseman. "Rodent Modeling of Alzheimer's Disease in Down Syndrome: In vivo and ex vivo Approaches". Frontiers in Neuroscience 16 (7.06.2022). http://dx.doi.org/10.3389/fnins.2022.909669.
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There are an estimated 6 million people with Down syndrome (DS) worldwide. In developed countries, the vast majority of these individuals will develop Alzheimer's disease neuropathology characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles within the brain, which leads to the early onset of dementia (AD-DS) and reduced life-expectancy. The mean age of onset of clinical dementia is ~55 years and by the age of 80, approaching 100% of individuals with DS will have a dementia diagnosis. DS is caused by trisomy of chromosome 21 (Hsa21) thus an additional copy of a gene(s) on the chromosome must cause the development of AD neuropathology and dementia. Indeed, triplication of the gene APP which encodes the amyloid precursor protein is sufficient and necessary for early onset AD (EOAD), both in people who have and do not have DS. However, triplication of other genes on Hsa21 leads to profound differences in neurodevelopment resulting in intellectual disability, elevated incidence of epilepsy and perturbations to the immune system. This different biology may impact on how AD neuropathology and dementia develops in people who have DS. Indeed, genes on Hsa21 other than APP when in three-copies can modulate AD-pathogenesis in mouse preclinical models. Understanding this biology better is critical to inform drug selection for AD prevention and therapy trials for people who have DS. Here we will review rodent preclinical models of AD-DS and how these can be used for both in vivo and ex vivo (cultured cells and organotypic slice cultures) studies to understand the mechanisms that contribute to the early development of AD in people who have DS and test the utility of treatments to prevent or delay the development of disease.
Rozprawy doktorskie na temat "DS rodent models"
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Ahumada, Saavedra José Tomás. "Craniofacial analysis of Down syndrome rodent models". Electronic Thesis or Diss., Strasbourg, 2024. http://www.theses.fr/2024STRAJ041.
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Les altérations les plus fréquentes et les plus caractéristiques du syndrome de Down (SD) sont les troubles de l'apprentissage et la dysmorphie crâniofaciale (CF). Le phénotype CF comprend des dimensions réduites de la tête, une brachycéphalie, une région orbitale médio-latérale réduite, une largeur bizygomatique réduite, un petit maxillaire, une petite mandibule et une variabilité individuelle accrue. Jusqu'à présent, les mécanismes cellulaires et moléculaires qui sous-tendent ce phénotype CF restent inconnus. Cette thèse, utilisant un nouveau panel de modèles de rats et de souris, a proposé de nouveaux gènes candidats pour le phénotype SD-CF. Nous avons confirmé le rôle de Dyrk1a dans la brachycéphalie du neurocrâne et identifié le surdosage du facteur de transcription Ripply3 pour le raccourcissement de la face médiane par la sous-régulation de Tbx1, un autre facteur de transcription impliqué dans des phénotypes similaires trouvés dans le syndrome de DiGeorge. Nous avons défini de nouveaux gènes sensibles au dosage responsables des malformations du SD-CF, et de nouveaux modèles ont été proposés pour sauver le phénotype SD-CF. Ces nouvelles connaissances pourraient également permettre de mieux comprendre les phénotypes cérébraux et cardiovasculaires spécifiques observés chez les mutants Tbx1 et les modèles de DSThe most frequent and distinctive alterations found in Down syndrome (DS) are learning disability and craniofacial (CF) dysmorphism. The CF phenotype includes reduced head dimensions, brachycephaly, reduced mediolateral orbital region, reduced bizygomatic breadth, small maxilla, small mandible, and increased individual variability. Until now, the cellular and molecular mechanisms underlying this CF phenotype remain unknown. This thesis, using a new panel of rats and mice models proposed new candidate genes for the DS-CF phenotype. We confirmed the role of Dyrk1a in neurocranium brachycephaly and identified the overdosage of the transcription factor Ripply3 for midface shortening through the downregulation of Tbx1, another transcription factor involved in similar phenotypes was found in Di George Syndrome. We defined new dosage-sensitive genes responsible for DS-CF malformations, and new models were proposed to rescue the DS-CF phenotype. This new knowledge may also lead to insights for specific brain and cardiovascular phenotypes observed in Tbx1 mutants and DS models