Behind the research
We use state of the art mouse genetic tools for ectopic expression, loss of function, and cell lineage tracing studies in specific populations of cells of the developing mouse kidneys to understand the molecular regulators that ensure normal kidney development and maintenance. These studies have provided insights into the potential genetic and cellular causes of cystic kidney diseases, including those that occur in Alagille Syndrome patients, and collecting duct disorders such as Nephrogenic Diabetes Insipidus.
Cystic kidneys diseases have been associated with mutations in over fifty genes. Alagille Syndrome is a multi-organ pediatric disorder in which small multi-cystic kidneys occur with variable penetrance in humans with mutations in genes coding for Notch signaling pathway components. We are using mouse models and cell culture systems to understand how Notch signaling suppresses renal tubular cyst formation and micro-adenoma formation. These studies are likely to reveal how Notch Signaling is linked to primary cilia and the cell cycle, and will provide insights into the mechanisms by Notch functions as a tumor suppressor in epithelial cancers.
Collecting duct disorders can be caused by the inheritance of mutant genes or may be triggered by medications in adults, such as lithium used to treat depression. Even though the collecting ducts are an essential component of kidneys that regulate water, electrolyte and pH homeostasis, the mechanisms regulating collecting duct differentiation into principal cells intermingled with intercalated cells are poorly understood. We have identified potential regulators of principal cell (PC) and intercalated cell (IC) differentiation by gene expression profiling of developing mouse kidneys “genetically enriched” for PC or IC lineage cells. These studies will generate knowledge of the molecular regulators of collecting duct differentiation and maintenance which will guide the design of cell replacement or molecular therapies to treat collecting duct disorders and boost adult collecting duct regenerative capacity.
July 2016, Dr. Kamesh Surendran received a $1.45 million R01 grant from the NIH's National Institute of Diabetes and Digestive and Kidney Diseases titled Molecular Regulators of Renal Collecting Duct Differentiation and Maintenance. These funds will be used to determine the essential transcriptional regulators that define the principal and intercalated cell types of the kidney collecting duct that are critical for water homeostasis and pH regulation. The knowledge gained will impact our understanding of both congenital/pediatric and acquired disorders of the collecting ducts such as Nephrogenic Diabetes Insipidus and renal tubular acidosis. These studies will also transform our understanding of kidney collecting duct cell differentiation and maintenance to provide knowledge that is fundamental to generating kidneys from patient-derived induced pluripotent-stem cells, which will improve the survival rates of end stage renal disease patients.