Добірка наукової літератури з теми "PD collagens"

BackgroundLeukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is an immune inhibitory receptor that binds collagen-like domains commonly found in extracellular matrix (ECM) collagens and complement component C1q. LAIR-1 is expressed on several immune cell types including activated T cells, B cells, NK cells, dendritic cells, and macrophages. Numerous cancer types including gastric, colon, ovarian, bladder, and others, upregulate collagens which enhances tumor growth, metastases, and invasion while actively suppressing antitumor immunity. While a soluble decoy, LAIR-2, is expressed in humans and competes with LAIR-1 for binding of collagen domains, excess LAIR ligands in the tumor often result in an immune suppressive environment.MethodsHere, we report on a novel immunotherapy approach combining NC410, a novel fusion protein consisting of two LAIR-2 molecules grafted on to an IgG1 antibody backbone, capable of targeting the tumor ECM and blocking LAIR-1 signaling; and bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (TGF-βRII or TGF-β ”trap”) fused via a flexible linker to the C-terminus of each heavy chain of an IgG1 antibody blocking programmed death ligand 1 (anti–PD-L1).ResultsWe have demonstrated that the combination of NC410 and bintrafusp alfa more effectively controls in vivo tumor growth of the collagen rich MC38 colon and EMT6 mammary carcinomas compared to either monotherapy. We demonstrate that this potent anti-tumor immune response is propagated through the synergy of activated tumor infiltrating lymphocytes and a repolarization of myeloid cells in the tumor microenvironment. MC38 tumors treated with the combination of NC410 plus bintrafusp alfa contained higher numbers of infiltrating T cells, NK cells, and M1 polarized macrophages.ConclusionsThis study highlights the synergy of reshaping the large suppressive myeloid cell populations often present in tumors with activation of adaptive T-cell immune responses dampened by checkpoint inhibition. The results also provide the rationale for the future evaluation of this combination therapy in the clinic.

BackgroundLAIR-1 is an immune inhibitory receptor expressed on several immune cell types including activated T cells, B cells, NK cells, macrophages, and dendritic cells. The ligands for LAIR-1 contain collagen-like domains which are commonly found in extracellular matrix collagens and complement component C1q. In numerous cancer types, including gastric, colon, ovarian, bladder, and others, upregulation of collagens has been shown to enhance tumor growth, metastases, and invasion while actively suppressing antitumor immunity. Although humans produce a natural, soluble decoy, LAIR-2, that competes with LAIR-1 for binding of collagen domains, excess LAIR ligands in the tumor often result in an immune suppressive environment.MethodsHere, we report on a novel immunotherapy approach which combined NC410, a LAIR-2-Fc fusion protein capable of blocking LAIR-1 signaling, and bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (TGF-βRII or TGF-β ‘trap’) fused via a flexible linker to the C-terminus of each heavy chain of an IgG1 antibody blocking programmed death ligand 1 (anti–PD-L1).ResultsWe demonstrate that the combination of NC410 and bintrafusp alfa more effectively controls in vivo tumor growth of the collagen rich MC38 colon carcinoma compared to either monotherapy. We hypothesize that this potent anti-tumor immune response is propagated through the synergy of activated tumor infiltrating lymphocytes and a repolarization of macrophages towards a tumoricidal phenotype. MC38 tumors treated with the combination of NC410/Bintrafusp alfa contained higher numbers of infiltrating CD4+ and CD8+ T cells and higher numbers of CD38+ and MHCII+ M1 polarized macrophages.ConclusionsThis study highlights the synergy of reshaping the large suppressive myeloid cell populations often present in tumors with activation of adaptive T-cell immune responses dampened by checkpoint inhibition. The results also provide the rationale for the future evaluation of this combination therapy in the clinic.AcknowledgementsBintrafusp alfa was kindly provided by EMD Serono under a CRADA with the NCI.Trial RegistrationN/AEthics ApprovalMice were maintained under pathogen-free conditions in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care guidelines. All animal studies were approved by the NIH Intramural Animal Care and Use Committee under protocol LTIB-038.ConsentN/A

BackgroundPeritoneal effluent contains clinically relevant substances derived from intraperitoneal production or transperitoneal transport, or both. The glycoproteinase matrix metalloproteinase 2 (MMP-2) cleaves denatured collagen and complements other collagenases in the degradation of fibrillar collagens. Elevated intraperitoneal levels of plasminogen activator inhibitor 1 (PAI-1) have been demonstrated to be present in patients with intra-abdominal adhesions. The aim of the present study was therefore to investigate the potential for effluent MMP-2 and PAI-1 to be used as markers of the development of peritoneal alterations. In addition, MMP-2 was analyzed in previously frozen effluent samples from a uremic rat model, in which data concerning the severity of peritoneal fibrosis were available.MethodsThis prospective, single-center cohort study included 86 incident peritoneal dialysis (PD) patients. All patients were treated solely with biocompatible dialysis solutions and underwent a standard peritoneal permeability analysis (SPA). The presence of local MMP-2 and PAI-1 production and the relationships between those markers and peritoneal transport parameters were analyzed. Furthermore, effluent interleukin 6 was analyzed as a marker of local inflammation.ResultsMedian effluent levels of 21.4 ng/mL for MMP-2 and 0.9 ng/mL for PAI-1 were found. The median dialysate appearance rates were 218.8 ng/min for MMP-2 and 9.6 ng/min for PAI-1. Local peritoneal production averaged 90% of effluent MMP-2 concentration and 74% of effluent PAI-1 concentration. Furthermore, correlations between peritoneal transport parameters and MMP-2 and PAI-1 were observed. Longitudinal follow-up showed no change for MMP-2 ( p = 0.37), but a tendency for PAI-1 to increase with the duration of PD ( p < 0.001). In rats, a significant relationship was present between the extent of peritoneal fibrosis and the appearance rate of MMP-2 ( r = 0.64, p = 0.03).ConclusionsThe foregoing data illustrate the potential of effluent MMP-2 and PAI-1 as biomarkers of peritoneal modifications, especially fibrosis; however, the components of peritoneal transport and local production should be clearly distinguished in every patient.

Muscle invasive bladder cancer (MIBC) is a malignancy with considerable heterogeneity. The MIBC tumor microenvironment (TME) is highly complex, comprising diverse phenotypes and spatial architectures. The complexity of the MIBC TME must be characterized to provide potential targets for precision therapy. Herein, an integrated combination of mass cytometry and imaging mass cytometry was used to analyze tumor cells, immune cells, and TME spatial characteristics of 44 MIBC patients. We detected tumor and immune cell clusters with abnormal phenotypes. In particular, we identified a previously overlooked cancer stem-like cell cluster (ALDH+PD-L1+ER-β−) that was strongly associated with poor prognosis. We elucidated the different spatial architectures of immune cells (excluded, infiltrated, and deserted) and tumor-associated collagens (curved, stretched, directionally distributed, and chaotic) in the MIBC TME. The present study is the first to provide in-depth insight into the complexity of the MIBC TME at the single-cell level. Our results will improve the general understanding of the heterogeneous characteristics of MIBC, potentially facilitating patient stratification and personalized therapy.

TPS2678 Background: Checkpoint inhibitors (CPI) targeting the PD1/PD-L1 axis significantly improved patient outcomes in stage IV non-small cell lung cancer (NSCLC). However, these patients will eventually develop resistance and progression. There is a need to identify novel treatment options. Poor response to PD-L1 antibody was correlated with increase in cancer-associated fibroblasts (CAF), which is known to interact with cytotoxic T cells (CTLs) by suppressing their function in a manner similar to regulatory T cells (Tregs). Production of cytokines by CAFs leads to impaired antitumor immunity by impairing CTL function (TGF beta) and prevent recruitment/mobilization of CTLs into tumors. These effects suggesting that CAF can be a therapeutic target in lung cancer resistant to checkpoint inhibitors. Pirfenidone (P) is approved to treat pulmonary fibrosis with anti-fibrotic effect by blocking the differentiation of fibroblasts into CAFs and suppress the production of TGF beta and TGF beta-induced signaling pathways/collagens. Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets PD-L1 and inhibits the interaction between PD-L1 and its receptors, PD-1 and B7-1 (CD80), both of which function as inhibitory receptors expressed on T cells. We proposed a phase I/II trial to test the combination of atezolizumab (A) with P in patients with recurrent non-small cell lung cancer (NSCLC) after progression with CPI. The primary objective of phase I is to determine the maximum tolerated (MTD) dose of P in combination with A and assess the safety and tolerability of this combination. The secondary objective is to determine the efficacy of AP in all NSCLC participants treated in this study. Exploratory objectives include the measurement of circulating levels of TGF beta and research in expression of CAF related proteins. Methods: The initial phase I will enroll 3 patients using P at 801 mg po TID. A will be at 1200mg iv every 3 weeks. If there is ≤ 1 DLT, the study will proceed to phase II If there are 2- 3 DLT, P will be reduced to 534 mg TID. If there is ≤ 1 DLT, then this dose will proceed to phase II. If there is 2-3 DLT, then the study will be terminated. The phase II will enroll 16 patients to assess efficacy. Main inclusion criteria are patients with recurrent NSCLC after progression with first-line therapy CPI with or without chemotherapy, measurable disease, ECOG 0-2, and adequate organ function. Clinical trial information: NCT04467723.

Abstract Soft tissue sarcomas (STS) are tumors of mesenchymal origin and include multiple sub-types such as undifferentiated pleomorphic sarcoma (UPS) which is the most frequent classification of STS. UPS is one of the most aggressive and recurrent sarcomas. The current standard of care for UPS patients remains surgical resection, radiotherapy, and chemotherapy, but many patients still develop recurrent tumors after these interventions. In addition, anti-PD-1 therapy has only been successful in a small fraction of patients with high levels of tumor infiltrating B and T cells, while immune excluded tumors showed poor responses. To understand why these tumors are frequently recurrent, it is essential to understand the characteristics of resistant tumor cells following standard treatment regimens in both immune excluded and immune infiltrated tumor microenvironments. We generated multiple mouse models that reflect the genetic alterations frequently found in patients via overexpression of oncogenes Ccne1 or Vgll3 in p53KO mesenchymal stem cells. Classification of the immune microenvironment of these models revealed that these driver genetics promote an immune excluded or immune infiltrated tumor microenvironment, respectively. We leveraged these two tumor models to understand the mechanisms of therapeutic resistance to common agents doxorubicin or anti-PD-1. We found that despite higher levels of baseline tumor infiltrating lymphocytes in Vgll3 tumors, anti-PD-1 failed to reduce tumor growth. Doxorubicin treatment resulted in a modest reduction of tumor volume in Ccne1 tumors, and more significantly in immune infiltrated Vgll3 tumors. To understand the transcriptional profiles of resistant tumor cells we harnessed single-cell RNA-sequencing (scRNA-seq) to characterize the least responsive model to determine if treatments had an impact on tumor cell expression profiles and which tumor clusters persist after treatment. scRNA-seq analysis revealed that different clusters of tumor cells were differently affected by anti-PD-1 and doxorubicin. While doxorubicin mainly affected tumor cells expressing collagens and matrix associated adhesion proteins, treatment with anti-PD-1 selectively reduced tumor cells enriched in interferon signaling pathways. Interestingly, tumor cells expressing high levels of extracellular matrix (ECM) remodeling genes remained unaffected and, in some cases, were enriched under both treatments. These results may suggest that tumor cells capable of ECM remodeling may shield tumor cells from chemotherapy agents and immune cells from immune checkpoint inhibitors and promote tumor recurrence. Therefore, these results highlight the need for investigation of combination therapies targeting extracellular matrix proteins in addition to immune checkpoint blockade. Citation Format: Marina T Broz, Marco DeSimone, Emily Ko, Roberta Piras, Jlenia Guarnerio. Uncovering transcriptional signatures of drug resistant tumor cells: Mechanisms of therapeutic resistance and opportunities for combination therapies [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A29.

BackgroundThe Leukocyte Associated Immunoglobulin-like Receptor 1 (LAIR1) is an immune inhibitory transmembrane glycoprotein expressed on lymphocytes and myeloid cells. The known ligands for LAIR1 are proteins containing collagen-like domains including collagen, complement component 1q (C1q), and stromal protein Colec12.1 2 3 Myeloid-derived suppressor cells (MDSC), tumor associated macrophages (TAMs), as well as collagens, are important contributors of the immune-suppressive tumor microenvironment, and LAIR1 expression is negatively correlated with patient survival in many solid tumors.4 These findings prompt us to investigate LAIR1 as a novel immuno-oncology target in collagen-rich tumors. Utilizing LAIR1 antagonist antibodies, we aim to mobilize anti-tumor immunity by changing the collagen-induced tolerogenic state of the immune cells into proinflammatory.MethodsThe mRNA expression levels of LAIR1, collagen, and C1q in diverse human cancers were analyzed using the TCGA database. LAIR1 protein expression on tumor infiltrated immune cells were measured by flow cytometry. Human tumor samples were obtained from Cooperative Human Tissue Network (CHTN) by the National Cancer Institute (NCI). Purified human T cells from healthy donors were stimulated with immobilized anti-CD3 in the presence of plate-coated human collagen I. Human monocyte-derived macrophages and dendritic cells (DC) were differentiated with M-CSF+IL-4 or GM-CSF+IL-4, respectively. Immune cell phenotypes were assessed by flow cytometry and cytokine secretion by Luminex.ResultsAnalysis of the TCGA database using signature genes specific to macrophages, T cells, DCs, and natural killer (NK) cells demonstrate that LAIR1 is highly expressed in most macrophage-infiltrated tumors and certain T cell-enriched tumors. LAIR1 and collagen are co-expressed at high levels in multiple macrophage-enriched tumors. Flow cytometry analysis of infiltrated immune cells from fresh tumor tissues showed that the highest level of LAIR1 protein expression was detected on TAMs, followed by monocytes, monocytic MDSCs, DCs, and lymphocytes. In vitro, LAIR1 antagonizing antibodies enhanced T-cell activation, proliferation, and IFNγ and TNFα production in comparison to isotype controls in the presence of collagen. Blocking LAIR1 interaction with collagen also decreased the expression of M2 markers such as PD-L1 and CD209 on monocyte-derived M2 macrophages. Additionally, treatment of monocyte-derived DCs by these antibodies increased the expression of the co-stimulatory protein CD86 and promoted the release of IL-12, a crucial cytokine for lymphocyte activation.ConclusionsThese in vitro data suggest that LAIR1 blockade could potentially reverse T-cell and myeloid immunosuppression mediated by collagen, demonstrating the therapeutic potential of anti-LAIR1 antagonistic antibodies.ReferencesMeyaard L. The inhibitory collagen receptor LAIR-1 (CD305). J Leukoc Biol 2008;83:799–803.Son M, et al. C1q limits dendritic cell differentiation and activation by engaging LAIR-1. PNAS 2012;109:3160–3167.Keerthivasan S, et al. Homeostatic functions of monocytes and interstitial lung macrophages are regulated via collagen domain-binding receptor LAIR1. Immunity 2021;54:1511–1526.Xu L, et al. Cancer immunotherapy based on blocking immune suppression mediated by an immune modulator LAIR-1. OncoImmunology 2020;9:e17404771–e17404779.

The extracellular matrix (ECM) of the brain is a dynamic structure made up of a vast network of bioactive macromolecules that modulate cellular events. Structural, organizational, and functional changes in these macromolecules due to genetic variation or environmental stressors are thought to affect cellular functions and may result in disease. However, most mechanistic studies to date usually focus on the cellular aspects of diseases and pay less attention to the relevance of the processes governing the dynamic nature of the extracellular matrix in disease pathogenesis. Thus, due to the ECM’s diversified biological roles, increasing interest in its involvement in disease, and the lack of sufficient compiled evidence regarding its relationship with Parkinson’s disease (PD) pathology, we aimed to compile the existing evidence to boost the current knowledge on the area and provide refined guidance for the future research. Here, in this review, we gathered postmortem brain tissue and induced pluripotent stem cell (iPSC)-related studies from PubMed and Google Scholar to identify, summarize and describe common macromolecular alterations in the expression of brain ECM components in Parkinson’s disease (PD). A literature search was conducted up until 10 February 2023. The overall hits from the database and manual search for proteomic and transcriptome studies were 1243 and 1041 articles, respectively. Following a full-text review, 10 articles from proteomic and 24 from transcriptomic studies were found to be eligible for inclusion. According to proteomic studies, proteins such as collagens, fibronectin, annexins, and tenascins were recognized to be differentially expressed in Parkinson’s disease. Transcriptomic studies displayed dysregulated pathways including ECM–receptor interaction, focal adhesion, and cell adhesion molecules in Parkinson’s disease. A limited number of relevant studies were accessed from our search, indicating that much work remains to be carried out to better understand the roles of the ECM in neurodegeneration and Parkinson’s disease. However, we believe that our review will elicit focused primary studies and thus support the ongoing efforts of the discovery and development of diagnostic biomarkers as well as therapeutic agents for Parkinson’s disease.

Pulmonary fibrosis is a progressive inflammatory disease with high mortality and limited therapeutic options. Previous genetic and immunologic investigations suggest common intersections between idiopathic pulmonary fibrosis (IPF), sarcoidosis, and murine models of pulmonary fibrosis. To identify immune responses that precede collagen deposition, we conducted molecular, immunohistochemical, and flow cytometric analysis of human and murine specimens. Immunohistochemistry revealed programmed cell death-1 (PD-1) up-regulation on IPF lymphocytes. PD-1+CD4+ T cells with reduced proliferative capacity and increased transforming growth factor–β (TGF-β)/interleukin-17A (IL-17A) expression were detected in IPF, sarcoidosis, and bleomycin CD4+ T cells. PD-1+ T helper 17 cells are the predominant CD4+ T cell subset expressing TGF-β. Coculture of PD-1+CD4+ T cells with human lung fibroblasts induced collagen-1 production. Strikingly, ex vivo PD-1 pathway blockade resulted in reductions in TGF-β and IL-17A expression from CD4+ T cells, with concomitant declines in collagen-1 production from fibroblasts. Molecular analysis demonstrated PD-1 regulation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Chemical blockade of STAT3, using the inhibitor STATTIC, inhibited collagen-1 production. Both bleomycin administration to PD-1 null mice or use of antibody against programmed cell death ligand 1 (PD-L1) demonstrated significantly reduced fibrosis compared to controls. This work identifies a critical, previously unrecognized role for PD-1+CD4+ T cells in pulmonary fibrosis, supporting the use of readily available therapeutics that directly address interstitial lung disease pathophysiology.

Ever since Sydney Brenner introduced Caenorhabditis elegans in the early 60s as a model system, this worm has contributed to many ground-breaking discoveries in science. It has served as an excellent model to study animal development, metabolism, longevity, neurobiology, and so on. Here, we have used C. elegans to understand the genetic regulation of skin barrier function and longevity. C. elegans dwells in an organically rich environment in the soil where it is exposed to various bacterial toxins and toxic chemicals. Under such conditions, it becomes very crucial for the worms to maintain the skin barrier integrity to prevent the diffusion of toxic molecules into the body. However, the components of skin that provide a barrier against diffusion of exogenous chemicals remain unknown. To identify genetic regulator(s) of the skin barrier function, we screened 93 collagens of C. elegans for their requirement in permeability barrier maintenance. We show that four collagens- DPY-7, DPY-8, DPY-9, and DPY-10 are essential for maintaining the skin barrier function of C. elegans skin. Loss of any of the 4 permeability-determining (PD) collagens leads to enhanced susceptibility of the nematode to paraquat (PQ) and antihelminthic drugs, levamisole, and ivermectin. Upon exposure to paraquat, PD collagen mutants accumulate more PQ, incur more damage, and death despite the robust activation of antioxidant machinery. We show that the permeability barrier maintained by PD collagens acts in parallel to FOXO transcription factor DAF-16 to enhance survival of insulin-like receptor mutant, daf-2. In all, this study shows that PD collagens regulate cuticle permeability by maintaining the structure of C. elegans skin and thus provide protection against exogenous toxic molecules. As PD collagens are essential for maintaining C. elegans cuticle structure, barrier function, and survival against exogenous toxic molecules, they must be under tight transcriptional v regulation. We screened 286 transcription factors expressed in hypodermis for their role in permeability barrier maintenance. We show that BLMP-1, T26A8.4, and LIR-1, zinc finger transcription factors, are important for maintaining the barrier function of the cuticle. blmp-1, T26A8.4, and lir-1 RNAi animals phenocopy PD collagens for survival on PQ, ivermectin, and levamisole. We further show that BLMP-1 and LIR-1 control cuticle permeability by regulating the expression of PD collagens and collagen processing enzyme protein disulfide isomerase pdi-2 in wild type animals. T26A8.4 RNAi altered expression of pdi-2 only. From this, we conclude that BLMP-1 and LIR-1 are the major regulators of the permeability determining collagens in C. elegans. Cuticle barrier function study shows that maintenance of cuticle ultrastructure and function is crucial for C. elegans survival. Recent studies show that C. elegans activates repair pathways and immune response upon wounding suggesting C. elegans can sense damage to the skin. We found that knockdown of PD collagens improved survival of C. elegans against osmotic stress, thermal stress, and P. aeruginosa infection while causing susceptibility to PQ. PD collagen animals also have a higher basal level of antioxidants, glyceraldehyde-5-phosphate dehydrogenase, and antimicrobial peptides. This indicated that there must be a cuticle structural and functional integrity surveillance system in the hypodermis. In microarray by Rohlfing et al., 2010, Patch-like Receptor (PTR) family expression was altered in dpy-9 and dpy-10 animals. By systematic analysis of 22 PTRs in dpy-9 animals for osmotic and hydrogen peroxide, we found that enhanced resistance of PD collagen animals is dependent on a specific receptor PTR-23. We found that PTR-23 works along with permeability determining factor LIR-1 to regulate thermal resistance in dpy-10 animals. In all, this study shows that C. elegans can perceive cuticle defects and trigger a stress response in a PTR-23 dependent manner. In nature, the only constant is change (Heraclitus, 500 BCE). To maintain an optimal life span, an organism needs to sense the ever-changing environment and adapt behaviorally and physiologically. This adaptation is coordinated by the nervous system vi of multicellular organisms. G-protein coupled receptors (GPCRs) are reported to sense environmental cues and regulate behavior and physiology. A recent life span study in Drosophila suggests GPCRs might regulate life span as well. In C. elegans, ablation of olfactory neurons-AWA, AWB, and AWC influence longevity suggesting the importance of olfaction and food sensing in the regulation of life span. We asked if specific olfactory GPCRs regulate C. elegans life span? We show that C. elegans longevity is regulated by a chemosensory GPCR STR-2, expressed in AWC and ASI amphid sensory neurons. This neuronal receptor controls lipid droplet homeostasis in the intestine. We show that STR-2 specifically regulates the expression of delta-9 desaturases, fat-5, fat-6, and fat-7 responsible for the production of monosaturated fatty acids (MUFA), an indicator of health and longevity, and diacylglycerol acyltransferase dgat-2. DGAT-2 catalyzes the final step of triglyceride synthesis i.e., transfer of a long-chain fatty acyl-CoA to diacylglycerol and therefore required for lipid droplet synthesis. Rescue of stored fat levels of GPCR mutant animals to wild type levels, with supplementation of the diet with a low concentration of glucose, rescues its life span phenotype. In all, we show that neuronal STR-2 GPCR facilitates metabolic adaptation to maintain the optimal life span at higher temperatures in C. elegans. In summary, we show that the optimal survival of C. elegans is dependent on intact cuticle barrier function and their ability to adapt to the constantly changing environment. The study of C. elegans barrier function highlights the importance of maintaining skin barricade by specific collagens. In mammalian skin, the stratum corneum of the skin act as an impermeable barrier against exogenous toxic molecules. Skin barrier defect has been associated with several diseases in humans such as Gaucher disease, atopic dermatitis, psoriasis, etc, and often associated with inflammation. C. elegans PD collagen mutants can serve as a tool to study toxicity or infiltration of high molecular weight toxic molecules such as commonly used herbicides and pesticides. C. elegans collagen skin could also be used to address permeability barrier function loss due to injury and, its impact on inflammation and wound healing responses. The study of life span regulation by a neuronal GPCR STR-2 suggests that GPCRs vii in the nervous system and other tissues could play an important role in determining the life span of an organism by regulating metabolic adaptation to environmental stimuli. Identifying the environmental cues, neural circuits, and genetic regulators could help us understand the mechanisms of aging better. This can help us design proper prognosis and treatment for age-associated diseases
IISc and Welcome DBT

The kidney has the vital function of excretion, and controls acid–base, fluid, and electrolyte balance. It also acts as an endocrine organ. Renal failure, with severe impairment of these functions, results from a number of different processes, most of which are acquired, although some may be inherited. Glomerulonephritis, which presents with proteinuria, haematuria, or both, may be accompanied by hypertension and impaired renal function. Pyelonephritis with renal scarring is the end result of infective disorders. Diabetes is now the commonest cause of end-stage renal disease (ESRD) in the UK and other systemic disease such as hypertension and collagen disorders can also affect the kidney. Polycystic kidney disease is the commonest inherited disorder leading to renal failure. Chronic renal failure implies permanent renal damage, which is likely to be progressive and will eventually require renal replacement therapy. Treatment of ESRD using haemodialysis (HD) and peritoneal dialysis (PD) can significantly improve physical and metabolic well-being and function but the proportion of those who continue to work with ESRD remains very low despite advances in treatment. Kidney transplantation enables many patients to return to normal lives including work. Reintegration of patients into the workforce following transplantation or dialysis offers an exciting and rewarding challenge to the wider health team. Renal disease is not within the top ten of the most costly diseases for employers and accounts for less than 1 per cent of sickness absence and incapacity claims. Urinary incontinence affects significant proportions of the workforce particularly women. Better management of urinary infections and calculi, prostatic obstruction, incontinence, and other complications of urinary tract disease has significantly reduced time lost from work.