Oxysterol-Binding protein like 7 in chronic kidney disease

慢性肾病中的氧甾醇结合蛋白如 7

基本信息

批准号：
10603088
负责人：
Jeffrey David Pressly
金额：
$ 7.4万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10603088
关键词：
ATP-Binding Cassette Transporters Adoption Advisory Committees Affect Agreement Apoptosis Autophagocytosis Autophagosome Binding Binding Proteins Cell membrane Cholesterol Cholesterol Esters Chronic Kidney Failure Collaborations Data Dedications Development Development Plans Disease Progression Endoplasmic Reticulum Ensure Environment Experimental Models Filtration Funding Golgi Apparatus Growth Immunoprecipitation Impairment In Vitro Individual Injury Institution Kidney Kidney Diseases Label Laboratories Learning Link Lipid Binding Lipids Mediating Membrane Membrane Fluidity Mentors Metabolic Diseases Metabolic Pathway Methodology Microscopy Modeling Movement Mus Names Pathogenesis Play Population Program Development Proteins Proteinuria Publications Regulation Renal function Renal glomerular disease Research Research Methodology Research Personnel Research Proposals Research Support Role Services Study models Testing Training Transfection Universities Vocational Guidance Zebrafish career career development cell type endoplasmic reticulum stress in vivo insight knock-down lipid metabolism lipid transport lipidomics medical schools meetings member mitochondrial dysfunction novel overexpression oxysterol binding protein pharmacologic podocyte preservation prevent research and development success

项目摘要

Project Summary Derangement of metabolic pathways involved in cellular lipid metabolism1 and ER stress2 have been shown to contribute to the pathogenesis of chronic kidney disease (CKD). We3-6 and others7 demonstrated that ATP- binding cassette transporter A1 (ABCA1) deficiency contributes to podocyte injury and disease progression of glomerular diseases of metabolic and non-metabolic origin. While ABCA1 deficiency is insufficient to cause podocyte injury, in vitro or in vivo, and proteinuria despite causing impaired cholesterol efflux and mitochondrial dysfunction5, overexpression of ABCA1 or pharmacological induction of ABCA1 (ABCA1i)5 was sufficient to rescue glomerular injury in proteinuric mice. Proximity labeling followed by immunoprecipitation of transfected potential targets led to identifying oxysterol binding to oxysterol-binding protein (OSBP) like 7 (OSBPL7) as the target of ABCA1i8. OSBPL7 is a member of a group of lipid-binding proteins involved in the movement of lipids between membranes8. OSBPs play a role in initiating autophagy9, cholesterol transfer from the endoplasmic reticulum (ER) to the Golgi, cholesterol efflux, and regulating ABCA1 expression10. However, if OSBPL7 is expressed in the kidney and if it is involved in regulating ABCA1-mediated cholesterol efflux or in the preservation of ER function in the podocyte has not been explored. The proposed research will investigate the function of OSBPL7 in podocytes. Based on my preliminary data, I hypothesize that OSBPL7 deficiency causes ABCA1-dependent impairment of cholesterol efflux and ABCA1- independent ER stress, thus linking OSBPL7 to podocyte injury and CKD progression. I propose the following specific aims using in vitro and in vivo approaches: (SA1) In vitro, determine the role of OSBPL7 in modulating ABCA1-dependent functions in podocytes. (SA2) In vitro, determine the mechanism by which OSBPL7 deficiency contributes to ER stress independent of ABCA1. (SA3) In vivo, determine if restoring renal OSBPL7 levels is sufficient to preserve renal function in col4a3 depleted zebrafish. I have created a comprehensive career development plan supported by my mentor and co-mentor to ensure my progress and success in this research proposal and facilitate my transition to an independent research career focused on lipid metabolism in association with glomerular disease. This plan includes (1) regular meetings with my mentor, co-mentors, and advisory committee, to provide research and career guidance, (2) research and career development seminars, learning new research methodologies, and (3) activities for career growth, including mentoring, publication, presentation, and application for independent research funding. My training will be conducted in an unparalleled academic environment at the University of Miami, Miller School of Medicine, which provides dedicated career development programs and necessary research support and supplies through my mentor, co-mentors, and institutional core services. This research and career development proposal is a product of my ambition and capacity to transition to an independent research career.

项目摘要已经显示有助于慢性肾脏疾病（CKD）的发病机理。 WE3-6等7证明了ATP- 结合盒式转运蛋白A1（ABCA1）缺乏症有助于足细胞损伤和疾病进展代谢和非代谢来源的肾小球疾病。而ABCA1缺乏不足以引起足细胞损伤，体外或体内，以及蛋白尿，尽管胆固醇外排和线粒体会受损功能障碍5，ABCA1的过表达或ABCA1的药理诱导（ABCA1I）5足以使营救蛋白尿小鼠的肾小球损伤。接近标记，然后对转染的免疫沉淀潜在的靶标导致鉴定氧蛋白酶与氧蛋白酶结合蛋白（OSBP）的结合，例如7（OSBPL7） ABCA1I8的目标。 OSBPL7是一组参与脂质运动的脂质结合蛋白的成员在膜之间8。 OSBP在启动自噬9，胆固醇转移从内质中发挥作用网状（ER）到高尔基体，胆固醇外排和调节ABCA1表达10。但是，如果OSBPL7是在肾脏中表达，并参与调节ABCA1介导的胆固醇外排或尚未探索在足细胞中的ER功能。拟议的研究将研究OSBPL7在足细胞中的功能。根据我的初步数据，我假设 OSBPL7缺乏会导致ABCA1依赖性胆固醇外排和ABCA1- 独立的ER应力，从而将OSBPL7与足细胞损伤和CKD进展联系起来。我建议遵循特定目的使用体外和体内方法：（SA1）体外，确定OSBPL7在调节足细胞中的ABCA1依赖性功能。（SA2）在体外，确定该机制 OSBPL7缺乏症导致与ABCA1无关的ER应力。（SA3）在体内，确定是否恢复肾脏 OSBPL7水平足以保留COL4A3耗尽斑马鱼的肾功能。我创建了一个由我的导师和联合学者支持的全面职业发展计划，以确保我的这项研究建议的进步和成功，并促进我向独立研究的过渡职业专注于与肾小球疾病相关的脂质代谢。该计划包括（1）常规与我的导师，联合主管和咨询委员会会议，以提供研究和职业指导，（2）研究与职业发展研讨会，学习新的研究方法和（3）职业活动增长，包括指导，出版，演示和独立研究资金的应用。我的培训将在迈阿密大学的无与伦比的学术环境中进行医学，提供专门的职业发展计划和必要的研究支持和通过我的导师，联席和机构核心服务来供应。这项研究和职业发展建议是我的野心和能力过渡到独立的能力的产物研究职业。