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c-Kit receptor signaling in the modulation of collecting duct function

Award Number: K01DK146206
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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c-Kit receptor signaling in the modulation of collecting duct function - PROJECT SUMMARY The current proposal is based upon our surprising finding that c-Kit is expressed in the kidney collecting duct. c-Kit regulates the proliferation and differentiation of stem cells; however, its role in in fully differentiated epithelial cells, such as in the collecting duct, remains elusive. Thus, this proposal aims to uncover the role of c- Kit receptor signaling in the modulation of kidney collecting duct function. The collecting duct is made up of principal cells (PC), which reabsorb water and salt, and intercalated cells (IC), which secrete protons. The collecting duct epithelial composition is altered in response to biochemical signals, thus affecting whole-body water, electrolyte and acid-base balance. For example, lithium treatment promotes PC differentiation into IC. Fewer PC prevents water reabsorption and leads to the development of nephrogenic diabetes insipidus (NDI), which can lead to severe dehydration and death. However, the precise mechanism by which epithelial cell fate is determined in the adult kidney collecting duct is not well understood. To address this question, I intend to utilize c-Kit “Sash” mice carrying the Wsh/Wsh mutation in a transcriptional element upstream of the KIT gene. This mutation results in reduced c-Kit expression in specific tissues and cells. I demonstrated for the first time that Sash mice have significantly reduced c-Kit expression in the collecting duct. I found that male “Sash” mice had an abnormally low urine pH, which could be explained by the fact that these mice have more acid-secreting IC and fewer water-absorbing PC in their collecting ducts. These findings led me to hypothesize that c-Kit receptor signaling in IC is required to maintain the normal cellular composition of the collecting duct, thus allowing the kidney to maintain proper extracellular volume, electrolyte, and acid-base homeostasis. In the current proposal I will determine: a) which isoforms of c-Kit and its ligand are expressed in the collecting duct; b) whether loss of c-Kit in the collecting duct affects renal function, and makes mice more susceptible to NDI, thus, mimicking disease states in the kidney; and c) the gene and protein networks associated with c-Kit receptor signaling in the kidney collecting duct under baseline and lithium-challenged conditions. Since c-Kit receptor activity is required for critical cellular processes including hematopoiesis and mast cell function, universal inhibition of c-Kit is not ideal therapeutically. This makes identifying subpopulations of receptors/ligands that are expressed in specific cell types or tissues critical to developing targeted therapeutics. Furthermore, my work will offer new directions for future studies on c-Kit regulation at the basic cell biological level, as well as providing a novel molecular basis for long-term drug discovery efforts to modulate c-Kit activity in the kidney, and other organs, to attenuate pathological processes caused by c-Kit receptor dysfunction.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $140,761 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/19/2026	NEW	$110,865
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	5/14/2026	NEW	$29,896
														Subtotal = $140,761

Grand Total All Awards = $140,761

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c-Kit receptor signaling in the modulation of collecting duct function

Award Number: K01DK146206

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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