Mechanisms of APOL1-mediated kidney disease

APOL1 介导的肾脏疾病的机制

• 批准号: 9319750
• 负责人: Leslie A Bruggeman
• 金额: $ 5.5万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-21 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319750
• 关键词: AIDS-Associated Nephropathy; APOL1 gene; African American; Aging; Alpha Cell; Anti-Retroviral Agents; Antiviral Response; Automobile Driving; Biological; Biopsy; Cell model; Chronic; Chronic Kidney Failure; Clinical; Complication; Data; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Disease model; Focal Segmental Glomerulosclerosis; Genes; Genetic; Genetic Variation; Genetic study; Genomics; Genotype; Goals; HIV; HIV Infections; HIV Seropositivity; HIV-1; Health; Human; In Vitro; Individual; Infection; Kidney; Kidney Cell Infection; Kidney Diseases; Link; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Odds Ratio; Pathogenesis; Pathogenicity; Pathologic; Pathway Analysis; Pathway interactions; Patients; Population; Positioning Attribute; Prevalence; Primates; Process; Publishing; Role; Sampling; Science; Stress; Testing; Transcend; Transcript; Transgenes; Transgenic Mice; Urine; Variant; Virus; base; clinically relevant; cohort; comparative genomics; differential expression; in vivo; kidney cell; mouse model; non-diabetic; novel diagnostics; novel therapeutics; podocyte; public health relevance; risk variant; therapy design; tool; transcriptome; urinary

 DESCRIPTION (provided by applicant): Despite the efficacy of combined anti-retroviral therapy (cART) in control of HIV infection, chronic, progressive kidney disease (CKD) causes significant morbidity in HIV patients. HIV-associated nephropathy (HIVAN) and focal segmental glomerulosclerosis (FSGS) remain the most prevalent pathological diagnoses in biopsies from HIV patients with CKD in contemporary cohorts. In the U.S., almost 90% of HIV infected subjects with CKD are African American. A landmark discovery associated genetic variation in the APOL1 gene with excess prevalence of advanced, non-diabetic CKD in African Americans, with published odds ratios for a recessive model of disease of 29 for HIVAN and 17 for primary FSGS. Not only do APOL1 risk genotypes independently accelerate CKD progression, subjects with APOL1 risk genotype and CKD do not benefit from current treatment. Although APOL1 kidney disease-associated variants are common (12% of African Americans carry the risk genotype), only a subset of these individuals develop advanced CKD, consistent with a "second hit" to initiate disease. Our prior studies established a requirement for direct HIV-1 infection of kidney cells in HIVAN pathogenesis, indicating HIV is a model "second hit." The biological mechanisms driving the association of APOL1 variants with CKD in African Americans are unknown. Studies published by us and other groups suggest APOL1 expressed in kidney cells mediates disease. Since APOL1 is a gene unique to humans and some primates, we have generated mouse models and cultured podocytes from urine of subjects with APOL1 risk genotypes to discover and model the mechanisms by which HIV-1 infection triggers CKD in susceptible individuals. These tools overcome the limited availability of human samples to test the following hypothesis: APOL1 has an endogenous function in the glomerular podocyte that is necessary to resist environmental stress and maintain podocyte health and these pathways are dysregulated in the presence of two risk variants where clinical disease manifests with the introduction of an environmental stress. We propose two specific aims to identify pathogenic pathways the mediate APOL1-associated kidney diseases: Aim 1: Use comparative genomics to identify candidate pathways mediating APOL1-associated kidney (podocyte) diseases. Aim 2: Use HIV-1 infection as a model trigger to characterize pathways mediating APOL1 regulated defenses to a CKD-inducing "second hit" to the podocyte. While focused on the APOL1 variant-HIV interactions, these causal pathways may identify mechanisms shared with other APOL1-associated CKDs. Our group is ideally positioned to undertake these studies, including established experts in HIVAN pathogenesis, genetics of chronic kidney disease in African Americans, and state-of-the-art genomic analysis. Understanding the mechanisms by which variant APOL1 associates with CKD is one of the most compelling questions in biomedical science, and these studies could potentially produce data that drives development of novel diagnostics and treatments for CKD in African Americans.