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Apolipoprotein L1 Interaction with SNARE Proteins in the Pathogenesis of Chronic Kidney Disease

载脂蛋白 L1 与 SNARE 蛋白在慢性肾脏病发病机制中的相互作用

基本信息

批准号：
10055541
负责人：
Sethu Madhavan Madhavan
金额：
$ 16.09万
依托单位：
OHIO STATE UNIVERSITY
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：
2020-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10055541
关键词：
APOL1 gene Accounting Address Affect African African American Age American Amino Acid Sequence Apolipoproteins Attenuated Autophagosome Binding Biochemical Biological Biological Models Cell Culture Techniques Cell Line Cells Cellular biology Chronic Kidney Failure Co-Immunoprecipitations Confocal Microscopy Cytoplasm Cytoskeleton Data Data Analyses Defect Development Diagnosis Dialysis procedure Disease Disease Progression End stage renal failure Event Expenditure Focal Segmental Glomerulosclerosis Follow-Up Studies Genes Genetic Predisposition to Disease Genetic Variation Goals Graft Survival High Density Lipoprotein Cholesterol Human Image Immune Immune System Diseases Immunofluorescence Microscopy Immunologic Factors Immunologic Tests Individual Interferon Type II Interleukin-1 beta Investigation Kidney Kidney Diseases Kidney Failure Knowledge Lead Learning Location Mass Spectrum Analysis Measures Mediating Medicare Membrane Fusion Minority Modeling Molecular NMR Spectroscopy Pathogenesis Pathologic Pathway interactions Patients Pattern Physicians Physiological Population Prevalence Prevention Protein Conformation Protein Family Proteins Proteinuria Proteomics Public Health Publishing Risk Role SNAP receptor Scientist Secondary to Stimulus Structural Models Structure TNF gene Testing Time Transgenic Mice United States Variant Vesicle base bioinformatics tool biological adaptation to stress clinically significant cytotoxicity design disease diagnosis experimental study genetic variant glomerulosclerosis human imaging immune activation in silico knock-down live cell imaging non-diabetic novel strategies novel therapeutic intervention patient population podocyte public health relevance recruit response risk variant skills stable cell line three dimensional structure tool trafficking

项目摘要

Summary Chronic kidney diseases (CKDs) are a major public health problem affecting more than 20 million people in the United States. African Americans are disproportionately affected by progressive CKDs, especially focal segmental glomerulosclerosis (FSGS). Genetic variants in the carboxy-terminal domain of APOL1 are associated with FSGS and other non-diabetic CKDs in populations with African ancestry. These variants change the amino acid sequence of APOL1 and explain much of this increased risk for CKDs in these populations. The pathogenetic mechanisms that lead from these APOL1 variants to CKD are not known. The carboxy-terminus of APOL1 interacted with VAMP8, an endosomal/lysosomal SNARE protein involved in vesicular trafficking and APOL1 kidney disease-associated variants attenuated the interaction with VAMP8 secondary to protein conformational changes induced by the variants. Like SNARE proteins, APOL1 localized to vesicular structures in the podocytes of the healthy human kidney. We hypothesize that APOL1:SNARE interaction is necessary to mitigate/attenuate podocyte stress response, and APOL1 variants disrupt functional SNARE interaction and mediate cytotoxicity. To test this hypothesis, we propose the following aims: First, we will use stable cell lines expressing APOL1 and healthy human kidneys to identify additional interacting SNARE proteins. We will use live-cell confocal microscopy to track APOL1:SNARE localization in various subcellular compartments in the presence and absence of immune stimuli. Second, we will investigate the cytotoxicity of reference and variant APOL1 proteins in the absence and presence of immune stimuli and reference APOL1 in the absence and presence of SNARE knockdown in cell culture models. Through these aims, I will obtain biochemical, imaging and proteomics data necessary to address our long term goal of identifying agents for the treatment of APOL1-associated kidney diseases. Understanding the molecular mechanisms by which APOL1 variants cause proteinuric CKD is essential for the development of new therapeutic strategies. I propose to use imaging and proteomics tools to study the pathological effects of APOL1 variants on its function and to learn bioinformatics tools to allow me to develop models to investigate CKD mechanisms. As a young physician-scientist, this project will help me to acquire new skills and knowledge while studying an important public health problem that afflicts my patients.

总结