Studies the genetics of kidney function and disease, particularly in the context of aging.
Our goal is to identify key genetic factors that contribute to the decline of function and damage in the aging kidney, to learn their role in the kidney, and to understand why variations of these factors lead to different outcomes. We do this by studying the natural genetic variation in mice and their association with different kidney phenotypes. Once causal genes are identified, we develop precision disease models for further study of the gene and to develop therapeutics that will slow down the decline of kidney function and development of disease.
Modifier Genes of Alport Syndrome
Alport syndrome is a monogenic disease leading to renal failure and early death. Despite that it is caused by a single mutation in either the Col4a3, Col4a4, or Col4a5 gene, there is a large variation in the age of onset and the severity of the disease, even in individuals with the same mutation. This is also true in mice where our Col4a4 mutant model shows differences in severity of the disease depending on the genetic background (PMID: 24522496). This suggests the involvement of modifier genes. Identifying these modifiers and understanding how they modulate the disease would be the first steps toward novel treatments. By crossing female mice containing a mutation in the X-linked Col4a5 with Diversity Outbred males, we created a population in which all males are hemizygous for the mutation and develop Alport syndrome in various degrees and all females are heterozygous for the mutation and disease depends on X-inactivation in the kidney. This population of 200 animals was extensively phenotyped at several time points and genetic analysis identified several candidate modifier genes, including Fmn1 and Rfx3 (PMID: 34045313).
To increase power and mapping resolution, we are currently studying a second population of 400 animals in an NIH funded study (RO1-DK131019). By combining both populations, we expect to identify additional candidate genes that we will further characterize for their role in the disease and the possibility of developing new therapies.
Modifier Genes of Diabetic Nephropathy
Diabetic nephropathy is the most common form of kidney disease and a consequence of diabetes. Several groups have identified factors (proteins/genes) that are associated with the progression of the disease in human patients. We are using mouse models to test the causality of several of these factors and try to understand their role in the disease.
Together with Andrzej Krolewski from the Joslin Diabetes Center, we are studying, HSD17B14, NBL1, EPHA2, and EFNA4. The study of the latter two proteins supported by NIH funding (RO1-DK131061). In addition, we have a long-term collaboration with the Mount Desert Island Biological Laboratory for studying factors such as KMO (PMID: 27020856) and HSP2.
The Aging Kidney
In most forms of kidney disease, age is an important factor. With age, the kidney undergoes changes that lead to a decline in function and makes it more susceptible to damage. By identifying these changes and develop therapies that slow them down, we may be able to preserve function and make them more resilient. Through our close ties with the JAX Center for Aging Research, we are studying various aspects in the aging mouse kidney and are developing tools to better quantify age-related changes and the impact of interventions on the kidney.
Through our NIA-funded Nathan Shock Center of Excellence in the Basic Biology of Aging (P30 AG038070) we looked at the changes in gene expression and protein expression in C57BL/6J mice and genetically diverse mice (PMID: 33687326) and are using spatial mass spectrometry to look at changes in lipids with age. We study histological changes (PMID: 24009241, 25353171) and develop high-throughput machine-learning methods that allow us to robustly quantify these changes (PMID: 30256126, 31220455, 33154175).
Our NIH-funded Senescence Tissue Mapping Center (U54-AG079753), which is part of the SenNet Consortium, uses state-of-the-art platforms to map and characterize senescent cells in several tissues, including the kidney. In a small study, we previously showed that senescence is dependent on genetic background in primary proximal tubule cells (PMID: 34201242), which can have implications on age-related decline in kidney function, but also on the effectiveness of senolytics, a new class of drugs that target senescent cells. We therefore study the effect of genetic background on senescence and senolytics in the kidney using the Shock Center and Senescence Tissue mapping Center resources.
Over the years, our NIA-funded Interventions Testing Program (U01-AG022308) identified several drugs that extend lifespan in mice with several of these expecting to have effects on the kidney (e.g. canagliflozin, captopril, thiosulfate). We are studying the effect of these drugs on the aging kidney in more detail.
One of our recent interests is the interaction between the aging kidney and bladder. The two are often viewed separately but remain inextricably entwined. To date, no studies have been conducted that fully investigate the correlation between kidney and bladder function, or whether gene/protein changes in one organ impact the other. To address this gap, we perform both functional and molecular assessments of the complete urinary tract across lifespan.
The UNE Keynote address by Ron Korstanje.