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The role of ARF6 in the progression of diabetic kidney disease

ARF6在糖尿病肾病进展中的作用

基本信息

批准号：
10412980
负责人：
Jamie Lin
金额：
$ 16.52万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10412980
关键词：
ADP-ribosylation factor 6 Actins Advisory Committees Affect Albumins Antigen-Antibody Complex Apoptosis Area Cancer Biology Cancer Center Cell Death Cell Line Cell Therapy Cells Cellular biology Chronic Chronic Kidney Failure Complement Data Development Development Plans Diabetes Mellitus Diabetic Nephropathy Diabetic mouse Disease Progression Disease model Environment Epithelial Cells Event Experimental Models Extravasation Genes Glucose Guanine Nucleotide Exchange Factors Guanosine Triphosphate Head Health Human Hyperglycemia In Vitro Injury Injury to Kidney Internal Medicine Intervention Investigation Kidney Diseases Kidney Failure Mediating Mentors Modeling Molecular Molecular Biology Molecular Target Monomeric GTP-Binding Proteins Morbidity - disease rate Morphology Mus Nephrology Oral Patients Persons Pharmacological Treatment Pharmacology Phenocopy Physicians Play Proteins Proteinuria Renal glomerular disease Research Resources Risk Role Scientist Signal Pathway Signal Transduction Stem cell transplant Stress Techniques Testing Therapeutic Training Training Activity Writing career development cell motility cellular oncology diabetic genome editing human disease in vitro Model in vivo inhibitor injured kidney dysfunction molecular oncology mortality mouse model mutant nephrin novel overexpression podocyte prevent response response to injury slit diaphragm targeted treatment trafficking transplantation therapy

项目摘要

Project Summary: Approximately 40% of patients with diabetes will develop diabetic kidney disease (DKD). Not only is it the leading cause of renal disease, but it is also associated with increased risk of patient morbidity and mortality. The diabetic milieu causes stress and injury to podocytes, glomerular epithelial cells, resulting in proteinuria and renal dysfunction. Thus, podocytes are key target cells that determine DKD progression; however, our limited understanding of podocyte signaling restricts our ability to develop cell-specific targeted therapy. We recently identified that ARF6 (ADP-ribosylation factor 6), a small GTPase protein, is involved with podocyte response to glomerular stress and deletion of ARF6 might be protective against podocyte damage in certain cases of kidney injury. The overall objective of this application is to define the role of ARF6 in DKD progression. This rationale is two-fold. First, increased ARF6 activity in other glomerular disease models mediates signaling pathways that result in effacement (i.e. a morphological adaptation seen in injured podocytes), and second, our preliminary data suggests that high glucose increases ARF6 activity. Thus, we hypothesize that hyperglycemia increases ARF6 activity which contributes to the progression of DKD. To this end, we will utilize diabetic models in vitro to determine if ARF6 has a role in podocyte effacement, detachment, and/or cell death. We will also identify the ARF6-GEFs (ARF6-guanine nucleotide exchange factors) that activate ARF6 by catalyzing ARF6-GDP to -GTP involved in effacement, detachment, and/or cell death. Using diabetic mice, we will specifically delete ARF6 from podocytes and determine the role of ARF6 in DKD. Last, we will explore pharmacologic interventions: ARF6 and ARF6-GEF inhibitors, to determine if ARF6 inhibition can prevent or augment DKD progression. Career Development Plan: The primary objective of this application is to support Dr. Lin’s career development into an independent physician-scientist in the area of cell signaling and molecular biology. Dr. Lin’s proposed training activities are in four areas 1) cell biology and signaling, 2) molecular techniques and genome editing, 3) diabetic mouse models of kidney injury, 4) scientific writing and oral presentations. Dr. Lin has assembled an exemplary mentoring and advisory team led by Dr. Farhad Danesh, Chief of Nephrology at MD Anderson Cancer Center (MDACC), a nationally recognized expert in the field of DKD and podocyte cell biology, complemented by Dr. Raghu Kalluri, Chair of Cancer Biology, Dr. Mien-Chie Hung, Chair of Molecular and Cellular Oncology, Dr. Elizabeth Shpall, Deputy Chair of Stem Cell Transplantation and Cellular Therapy, and Dr. David Tweardy, Head of the Division of Internal Medicine. MDACC, a center of excellence in cutting edge research, will provide an opportune, resource abundant training environment for Dr. Lin.

项目总结：大约40%的糖尿病患者会发展为糖尿病肾病（DKD）。不