权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Biological function of testican-2 in podocyte health

testican-2 在足细胞健康中的生物学功能

基本信息

批准号：
10599209
负责人：
Donghai Wen
金额：
$ 16.96万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599209
关键词：
Actins Adhesions Adriamycin PFS Advisory Committees Affinity Albuminuria Aorta Area Attenuated Binding Biological Markers Biological Process Biology Blood Boston Cell surface Cells Chronic Kidney Failure Circulation Clinical Research Creatinine Cytoskeleton Data Dedications Diabetic Nephropathy Emerging Technologies Enzyme-Linked Immunosorbent Assay Etiology Extracellular Matrix Extracellular Matrix Proteins Fellowship Focal and Segmental Glomerulosclerosis Future General Population Genes Genetic Glomerular Filtration Rate Glycoproteins Goals Grant Health Human ITGB3 gene Immunoassay Immunofluorescence Immunologic In Vitro Individual Injury Integrin alphaVbeta3 Interferometry Interstitial Nephritis Kidney Kidney Diseases Knowledge Ligands Manuscripts Mass Spectrum Analysis Measures Mediating Mentors Mentorship Microscopy Mus Nephrology Patients Peptides Physicians Physiology Play Prognosis Proteins Proteomics Public Speaking Publications RGD (sequence)Renal glomerular disease Research Research Personnel Research Training Role Sampling Science Scientist Serum Signal Transduction Site-Directed Mutagenesis Structure Structure of renal vein Surface Tertiary Protein Structure Testing Therapeutic Time Tissue Sample Tissues Training Vitronectin Writing aptamer career career development cohort experience glomerulosclerosis human subject in vivo inhibitor insight kidney biopsy kidney metabolism knock-down multidisciplinary novel novel therapeutic intervention overexpression podocyte population based prognostic protective effect protein protein interaction single-cell RNA sequencing therapeutic target tissue biomarkers training opportunity translational approach

项目摘要

PROJECT SUMMARY/ABSTRACT Using a proteomic screen of samples obtained from the aorta and renal vein of human subjects, we recently identified testican-2 as a podocyte-derived protein that is released by the kidney into circulation. Further, we found that testican-2 levels are positively correlated with estimated glomerular filtration rate (eGFR) and higher baseline levels of testican-2 are associated with less eGFR loss over time, advancing the concept that testican-2 provides insight on kidney health and prognosis. However, the biological function of testican-2 in podocytes and the kidney is unknown. Encoded by the SPOCK2 gene, testican-2 is a glycoprotein that is a component of the extracellular matrix (ECM). In preliminary data generated by the PI, we find that testican-2 attenuates podocyte injury induced by Adriamcyin both in cultured human podocytes and mice. We further find that testican-2 binds to another ECM protein vitronectin and reduces its binding affinity to integrin αVβ3, an adhesion protein on the podocyte surface. Using these findings as a springboard, this proposal will test the central hypothesis that testican-2 plays a functional role in podocyte health by reducing vitronectin-mediated integrin αVβ3 activation and signaling: Aim 1) To determine the protein domain required for testican-2 binding with vitronectin; Aim 2) To determine the impact of testican-2 on integrin αVβ3 activation and podocyte injury; and Aim 3) To assess testican-2 expression in patients with diabetic nephropathy and primary focal segmental glomerulosclerosis. The candidate, Dr. Wen, is deeply committed to a career in academic nephrology. He previously pursued broad-based research training in nephrology, with a particular focus on renal physiology. Since pursuing a nephrology fellowship in 2018, he has shifted his focus to a new area—the biological function of testican-2 in podocyte health, with both basic and translational approaches. Dr. Wen’s immediate career goals include acquiring content knowledge and hands-on experience with emerging technologies in the areas of podocyte biology; protein-protein interaction and structure; and blood and tissue biomarkers. In addition, he seeks training with public speaking and grant and manuscript writing. Dr. Wen’s long-term career goal is to become an independent physician-scientist who pursues both basic and translational approaches to develop new therapeutic strategies for patients with podocytes injury, and kidney disease in general. He will benefit from complementary mentorship from Eugene Rhee (mentor; Chief, MGH Nephrology), an expert in kidney metabolism and biomarkers; and Martin Pollak (co-mentor, Chief, BIDMC Nephrology), a leader in genetics and podocyte biology. Drs. Wen, Rhee, and Pollak will meet frequently to discuss both science and career development and have clearly identified aspects of the research proposed that will form the basis of his independent career. An advisory committee will provide additional guidance, evaluate progress, and help plan future directions.

项目总结/文摘