Monday, December 30, 2024
12/30/2024
PROJECT SUMMARY/ABSTRACT Alport syndrome is a human hereditary glomerulonephritis, which in most cases, results in end-stage renal disease. It is the most common inherited glomerular disease leading to renal failure and is caused by mutations in any one of the genes encoding a3, a4, or a5 chains of type IV collagen (COL4A3, COL4A4, and COL4A5, respectively). There is large variation in the age of onset and severity of the disease, even between patients with similar mutations. Studies in mice have shown that the renal phenotype is highly dependent on the genetic background. It is widely accepted that modifier genes contribute to this variation, which could represent a source of novel therapeutic targets in Alport syndrome and other renal diseases. We identified human-relevant modifier genes in a small cohort of genetically diverse mice with a Col4a5 mutation (leading to X-linked Alport syndrome (XLAS)) and validated that decreased expression of one of these genes, Fmn1, leads to a less severe renal phenotype. We further found that two of the candidate modifier genes (Pik3r1 and Dgke) modulate other forms of kidney disease, including diabetic nephropathy and hematolytic urea syndrome. In this application we will discover novel candidate modifier genes of XLAS by high-resolution genetic mapping in a large genetically diverse XLAS mouse cohort and confirm the translational relevance of the modifiers in humans. The functional impact and causality of the modifier genes will be assessed in preclinical mouse models of XLAS and other forms of kidney disease. We will generate a large, genetically diverse XLAS mouse population that, combined with our previous population, will allow us gene-resolution mapping of modifier loci (Aim 1). Whole exome sequencing and targeted testing for the detection of the most likely candidate modifier genes in human XLAS pedigrees will be conducted to confirm the translational relevance of the candidate modifier genes found in our mouse studies (Aim 2). We will use available knockout resources and/or CRISPR- Cas9 gene editing to test causality of as many as five candidate genes in the XLAS mouse model (Aim 3A). We will further test these modifier genes for causality in mouse models of two common forms of kidney disease: diabetic nephropathy and focal segmental glomerulosclerosis syndrome (Aim 3B). Identification of the genes responsible for the onset and severity of disease will provide meaningful insights into understanding the molecular events underlying the pathogenesis of kidney disease and provide the basis for developing novel therapeutic strategies.
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