权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Intracellular functions of APOL1 in the kidney

APOL1 在肾脏中的细胞内功能

基本信息

批准号：
10383979
负责人：
Leslie A Bruggeman
金额：
$ 56.49万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-23 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10383979
关键词：
AIDS-Associated Nephropathy Advanced Development Advocate African American Alleles Apolipoproteins Attenuated Bacterial Artificial Chromosomes Biochemical Biochemical Pathway Biological Models Biological Process Cell Adhesion Cell Line Cell Survival Cells Chronic Kidney Failure Clinical Clustered Regularly Interspaced Short Palindromic Repeats Data Development Disease Disease model Endosomes Environment Event Exposure to Focal Segmental Glomerulosclerosis Functional disorder Future Gene Expression Gene Expression Profiling Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Risk Genetic Transcription Genotype Goals HIV HIV Infections Human Hypertension IRF3 gene Immune Immune response Immune signaling In Vitro Individual Inheritance Patterns Inherited Injections Injury Interferons Investigation Kidney Kidney Diseases Knock-out Link Lupus Nephritis Mediating Methods Modeling Mus Outcome Study Pathogenesis Pathogenicity Pathology Pattern recognition receptor Phenotype Poly I-C Prevalence Prevention strategy Process Receptor Activation Renal function Risk Role Signal Transduction Stimulus Stress TLR3 gene Testing Time Toll-like receptors Transgenic Mice United States Variant Vesicle Virus Virus Diseases Work adaptive immune response biological adaptation to stress cytotoxicity density disease stressor disorder risk environmental stressor gain of function gene environment interaction genetic variant high risk immune activation in vivo in vivo Model induced pluripotent stem cell innate immune pathways kidney biopsy loss of function mouse model non-diabetic novel novel therapeutics podocyte protective effect racial health disparity recessive genetic trait response risk variant stressor targeted treatment therapy design trafficking trait treatment strategy

项目摘要

ABSTRACT Chronic kidney disease (CKD) in African Americans is one of the largest racial health disparities in the United States. The cause for the increased risk has been attributed to recessive inheritance of allelic variants in the gene for apolipoprotein L1 (APOL1). These APOL1 variants, known as G1 and G2, do not cause CKD on their own, but CKD is caused by a combination of the inherited genetic risk plus exposure to a triggering environmental stressor (a gene-environment interaction). Despite the association of CKD risk with APOL1 variants more than ten years ago, the biological function of APOL1 in the kidney and the mechanism of pathogenesis in the setting of a disease stressor remain unclear. Our long-term goal is to understand the genetics and biochemical mechanism of CKD in African Americans caused by these APOL1 polymorphisms. To accomplish this goal, we are studying HIV-associated nephropathy (HIVAN), the CKD most strongly associated APOL1 variants, and the only CKD where the environmental stressor is known (HIV infection). HIVAN is an ideal disease model to dissect biochemical pathways and cellular events intersected by APOL1 function, viral infection, and CKD. Our recent studies have demonstrated, for the first time, a function for the common APOL1 allele, known as G0, in providing protection against podocyte losses in HIVAN. Since APOL1 risk is a recessively inherited trait, this suggests CKD may be caused, in part, by a loss-of-function process (i.e. absence of G0). In new preliminary data, G0 appears to associate with Toll-like receptors (TLRs) in intracellular vesicles containing HIV and facilitate signaling events initiated by interferon regulatory factor (IRF)-3, and these processes were absent with the APOL1 risk variants. Methods will use established in vitro HIV infection of human podocyte cell lines, in vivo models of HIVAN and BAC-APOL1 transgenic mice that replicate endogenous human APOL1 expression. Aims will examine both initial response to HIV infection in podocytes, and long-term in vivo studies of intercrosses between the HIVAN and BAC-APOL1 transgenic mice evaluating effects on renal function and pathology. These studies also will establish temporal and magnitude of stressor-induced APOL1 expression, the mechanism of the altered innate immune activation through TLRs to IRF-3/7 signaling, and effect on podocyte phenotype (survival and cell adhesion). The dominance of the G0 protective effect over the risk variant dysfunction will be tested in podocytes and mouse models co-expressing G0 and the risk variants. These studies should advance our understanding of gain- versus loss-of-function mechanism associated with the recessive inheritance of APOL1 risk alleles, and the necessity of induced APOL1 expression to drive stress responses. Determining the contribution of G0 function versus risk variant dysfunction will have important clinical impact on further therapy design, as it will establish whether replacement of G0 or suppression of the risk variants would be the more effective strategy.

摘要