Genetic Determinants of Focal Segmental Glomerulosclerosis in Mouse and Humans
Abstract
The goals of this project are to identify genetic determinants of focal segmental glomerulosclerosis (FSGS). We have shown that the development nephropathy in the HIV-1 transgenic mice (TgFVB) is highly strain dependent. Linkage mapping in murine crosses have shown that there are at least 4 FSGS susceptibility loci among inbred strains. Furthermore, F1 hybrids between TgFVB and other inbred strains show highly variable penetrance of nephropathy, indicating the feasibility of mapping genes using F1 hybrids for association mapping. Our previous work, we identified a Candidate geneSsbp2, (PMID: 34893534) associated with the susceptibility to HIV associated nephropathy. We now have Ssbp2 null mice generated and using these mice we are able to knock out Sspb2 either globally or we can specifically target specific cells including the podocyte where Ssbp2 is highly expresses. We are in the process of generating Ssbp2 null mice on two HIVAN resistant strains (C57BL/10J and C57BL6/NJ) and two susceptible strains (A/J and FVB/NJ). We are immunophenotyping and transcriptionally profiling the resident lymphocyte populations in the HIV-1 transgenic mice (TgFVB) and demonstrate a population of CD107a+ activated lymphocytes residing in the kidney of the TgFVB mice. We have demonstrated these CD107a+ lymphocytes are involved in kidney damage leading to elevated levels of proteinuria. Our interim analysis of genetic modifiers of APOL1 high risk genotypes, demonstrated the APOL1 high risk genotype was associated with an increased with an increased risk of C1q nephropathy, FSGS, and hypertension-attributed chronic kidney disease (CKD). We observed a significant enrichment of rare missence variants in the inflammasome gene-set was identified in individuals with high risk APOL1 genotypes and kidney disease.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2023
- Accession Number
- AD1213001
Entities
People
- Ali G. Gharavi
Organizations
- Columbia University