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：
10170336
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/10170336
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 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/antagonist 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.

项目摘要：大约 40% 的糖尿病患者会患上糖尿病肾病 (DKD)。它不仅是肾脏疾病的主要原因，而且还与患者发病率和患病风险增加有关。糖尿病环境会对足细胞、肾小球上皮细胞造成压力和损伤，从而导致死亡。因此，足细胞是决定 DKD 进展的关键靶细胞。然而，我们对足细胞信号传导的有限了解限制了我们开发细胞特异性靶向药物的能力我们最近发现 ARF6（ADP-核糖基化因子 6）是一种小 GTP 酶蛋白，与治疗有关。足细胞对肾小球应激的反应和 ARF6 的缺失可能可以保护足细胞免受足细胞损伤本申请的总体目标是确定 ARF6 在 DKD 中的作用。这个理由有两个：首先，其他肾小球疾病模型中 ARF6 活性增加。介导导致消失的信号通路（即在受伤的动物中看到的形态适应）足细胞），其次，我们的初步数据表明高葡萄糖会增加 ARF6 活性。继续认为高血糖会增加 ARF6 活性，从而导致 DKD 的进展。最后，我们将利用体外糖尿病模型来确定 ARF6 是否在足细胞消失、脱离、我们还将鉴定激活 ARF6-GEF（ARF6-鸟嘌呤核苷酸交换因子）。 ARF6 通过将 ARF6-GDP 催化为 -GTP 参与消失、脱离和/或细胞死亡。小鼠，我们将特异地从足细胞中删除 ARF6，并确定 ARF6 在 DKD 中的作用。探索药理学干预措施：ARF6 和 ARF6-GEF 抑制剂，以确定 ARF6 抑制是否可以预防或促进 DKD 进展。职业发展计划：此应用程序的主要目标是支持林博士的职业发展林博士提议成为细胞信号传导和分子生物学领域的独立医师科学家。培训活动涉及四个领域：1) 细胞生物学和信号传导，2) 分子技术和基因组编辑，3) 糖尿病小鼠肾损伤模型，4) 林博士整理了科学写作和口头报告。 MD 安德森癌症中心肾病科主任 Farhad Danesh 博士领导的模范指导和咨询团队国家DKD和足细胞生物学领域公认专家中心（MDACC）补充作者：Raghu Kalluri 博士，癌症生物学系主任，Mien-Chie Hung 博士，分子和细胞肿瘤学系主任，干细胞移植和细胞治疗副主席 Elizabeth Shpall 博士和 David Tweardy 博士，尖端研究卓越中心 MDACC 内科主任将提供服务。为林博士提供机会、资源丰富的培训环境。