Oxysterol-Binding protein like 7 in chronic kidney disease

慢性肾病中的氧甾醇结合蛋白如 7

• 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
• 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

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 已经显示出参与细胞脂质代谢1和ER应激2的代谢途径的紊乱 导致慢性肾病（CKD）的发病机制。我们3 -6和其他人7证明了ATP- 结合盒转运蛋白A1（ABCA 1）缺乏导致足细胞损伤和疾病进展， 代谢和非代谢来源的肾小球疾病。虽然ABCA 1缺乏不足以导致 足细胞损伤，在体外或体内，和蛋白尿，尽管造成受损的胆固醇流出和线粒体 功能障碍5、ABCA 1过表达或ABCA 1的药理学诱导（ABCA 1 i）5足以 挽救蛋白尿小鼠的肾小球损伤。邻近标记，随后免疫沉淀转染的 潜在的靶点导致鉴定氧固醇结合到氧固醇结合蛋白（OSBP）样7（OSBPL 7）作为 ABCA 1 i8的目标。OSBPL 7是参与脂质运动的一组脂质结合蛋白的成员 在膜之间8. OSBPs在启动自噬9，胆固醇从内质网转移中起作用。 内质网（ER）的高尔基体，胆固醇流出，并调节ABCA 1的表达10。但是，如果OSBPL 7是 在肾脏中表达，如果它参与调节ABCA 1介导的胆固醇流出或参与 还没有研究足细胞中ER功能的保存。拟议的研究将 研究OSBPL 7在足细胞中的功能。根据我的初步数据，我假设 OSBPL 7缺乏导致ABCA 1依赖性胆固醇流出障碍，ABCA 1- OSBPL 7与足细胞损伤和CKD进展相关。我建议 （SA 1）在体外，确定OSBPL 7在细胞内的作用， 调节足细胞中的ABCA 1依赖性功能。(SA2)在体外，确定 OSBPL 7缺陷导致ER应激，而不依赖于ABCA 1。(SA3)在体内，确定是否恢复肾脏 OSBPL 7水平足以保护col 4a 3缺失的斑马鱼的肾功能。我已经创建了一个 全面的职业发展计划，由我的导师和共同导师支持，以确保我的 在这项研究计划的进展和成功，并促进我过渡到一个独立的研究 主要研究与肾小球疾病相关的脂质代谢。该计划包括（1）定期 与我的导师、共同导师和咨询委员会会面，提供研究和职业指导，（2） 研究和职业发展研讨会，学习新的研究方法，以及（3）职业发展活动 增长，包括指导，出版，演示和申请独立的研究资金。我 培训将在迈阿密大学米勒学院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， 通过我的导师，共同导师和机构的核心服务供应。这项研究和事业 发展提案是我向独立转型的雄心和能力的产物 研究生涯。