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BLR&D Merit Review Research Career Scientist (RCS) Award (IK6)

BLR

基本信息

批准号：
10618237
负责人：
AMBRA POZZI
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618237
关键词：
Affect American Animal Model Area Award Binding Biology CCL2 gene Cell Nucleus Cells Cessation of life Chromatin Chronic Kidney Failure Clinical Management Collagen Collagen Receptors Collagen Type IV DDR1 gene DNA Deposition Development Disease Doctor of Philosophy Down-Regulation ECM receptor End stage renal failure Epidermal Growth Factor Receptor Etiology Extracellular Matrix Fibrosis Funding Funding Agency Generations Genetic Genetic Transcription Goals Health Healthcare Homeostasis Human In Vitro Inflammatory Injury Injury to Kidney Integrin Inhibition Integrins International Journals Kidney Kidney Diseases Ligands Mediating Medicine Military Personnel Mission Morbidity - disease rate NADPH Oxidase Names National Institute of Diabetes and Digestive and Kidney Diseases Nephrology Nuclear Nuclear Translocation Outcome Oxidative Stress Pathology Pathway interactions Peer Review Penetration Peptides Pharmaceutical Preparations Phosphorylation Play Pre-Clinical Model Privatization Production Profibrotic signal Protein Tyrosine Phosphatase Publications Publishing Quality of life RNA-Binding Proteins Reactive Oxygen Species Receptor Activation Regulation Renal function Research Ribonucleoproteins Role Scientist Sclerosis Signal Transduction Site Societies T-cell protein tyrosine phosphatase Therapeutic Transforming Growth Factor beta Receptors Tyrosine Phosphorylation United States National Institutes of Health Universities Veterans Work active duty antifibrotic treatment base career clinical investigation discoidin receptor editorial fused in sarcoma improved in vivo indexing inhibitor kidney fibrosis medical schools mortality mouse development novel novel strategies prevent professor programs promoter receptor recruit small molecule small molecule inhibitor transcription factor

项目摘要

The PI is an expert in extracellular matrix (ECM) receptor biology and how these receptors control ECM homeostasis in health and disease. As progressive accumulation of ECM leads to fibrosis, the PI goal is to determine the mechanisms whereby ECM receptors control matrix synthesis/degradation in order to devise more effective anti-fibrotic therapies. Among the matrix receptors the PI focuses on integrins (VA Merit Review) and discoidin domain receptors (DDRs) (NIH/NIDDK R01) in the regulation of collagen synthesis and degradation in kidney injury. The PI’s group has evidence that the collagen receptor integrin α1β1 is a negative regulator of fibrosis and it plays a protective role by: 1) downregulating the activation of the TGF-β receptor in a ligand independent manner and dampening Smad-dependent pro-fibrotic signaling; 2) inhibiting the activation of the EGF receptor; 3) negatively regulating the assembly of the NADPH oxidase thus reducing oxidative stress; and 4) preventing the phosphorylation and nuclear translocation of the ribonucleoprotein Fused in Sarcoma (FUS) (VA Merit Review). In contrast to integrin α1β1, integrin α2β1 and DDR1 are postive regulators of fibrosis and studies from the PI group indicate that genetic deletion of integrin α2β1 or DDR1 protects mice from the development of kidney fibrosis after injury. The PI’s group provides strong evidence that the deleterious action of these two matrix receptors resides in their ability to activate pro-inflammatory (MCP-1) and pro-fibrotic (Stat-3) downstream signaling. In addition, the PI provides the novel finding that DDR1 can regulate collagen production by translocating to the nucleus where it localizes to chromatin to promote the transcription of collagen. Based on these findings, the PI’s goal is to devise peptide-based inhibitors and small molecule inhibitors to target these receptors and/or their downstream signaling. The PI’s group has strong evidence that small-molecule and peptide-based approaches to inhibit integrin α2β1 and FUS nuclear translocation, respectively, have a great promise to be used as anti-fibrotic approaches in vitro and in animal models. Based on these exciting results the PI is currently refining strategies to prevent and ideally halt kidney fibrosis and identifying novel and potentially targetable molecules selectively regulated by integrins and DDRs. The PI studies are published in high rated journals including Journal of American Society of Nephrology, Kidney International, Matrix Biology, Journal of Clinical Investigation, to name a few. In order to be successful, the PI has assembled a team of cell biologists, medicinal chemists, experts in the generation of cell-penetrating peptide- mediated therapeutic molecule, and nephrologists both at the University and VA site. The PI’s area of research is highly relevant to our Veterans because kidney fibrosis and consequent end stage kidney disease are commons in active duty military and Veterans. The work performed by the PI and her team will lead to the development of novel strategies to halt and ideally prevent kidney fibrosis and, hence, improve the quality of lives of our Veterans.

PI是细胞外基质（ECM）受体生物学和这些受体如何控制ECM的专家