Friday, November 22, 2024 11/22/2024

Uncovering cargo and cell type specific molecular mechanisms of renal tubular epithelial transport

Award Number: R01DK131020
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT/PROJECT SUMMARY Mutations in actin associated motor protein nonmuscle myosin II isoform A (NM2A), encoded by MYH9, have been associated with kidney disease in at least one-third of the patients. Previous work focused on the role of Myh9 in podocyte actin cytoskeleton. Our recent work has established a critical role for Myh9 and Myh10 genes in the adult mouse renal epithelium. Inducible, conditional knockout (cKO) of Myh9&10 in adult mouse renal epithelial cells resulted in progressive tubular disease with transport defects in the thick ascending limb (TAL). Loss of Myh9&10 proteins resulted in deregulated transport of GPI-anchored protein uromodulin (UMOD), along with upregulation of ER stress and unfolded protein response pathways, promoting tubular injury and disease in Myh9&10 cKO mice. In addition, Na+ K+ 2Cl- cotransporter (NKCC2) does not localize to the apical membrane and we observe a progressive decline in NKCC2 protein levels in Myh9&10 cKO mouse kidneys. Single paralog renal tubule specific Myh9-PT cKO mice also develop moderate tubular kidney disease, but podocyte-specific Myh9-cKO in mice does not lead to kidney disease. Here, we propose to determine the cell type specific roles for Myh9 in TAL epithelium and podocytes and their contribution to kidney disease. We have generated novel, immortalized TAL cell culture system to enable long-term in vitro cargo transport studies. We will utilize the single paralog Myh9 and Myh10 pan-renal tubular (PT) cKO, TAL-specific cKO and podocyte-specific Myh9-cKO mouse models to enable dissection of the mechanistic and physiological roles for NM2 in two different kidney cell types. Effects of high salt diet and sex-dependent variations on disease pathology will be tested. A mouse model harboring Myh9-cKO in both podocytes and TAL epithelium will be characterized to determine the synergistic pathological effect, that will better model a severe form of MYH9-RD with complete loss of function. Our proposed work will uncover the critical roles for NM2 motor proteins in specialized cargo transport and will identify novel mechanisms involved in MYH9 mutation associated kidney diseases and other TAL-associated kidney disorders.


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: 2024 ( Subtotal = $358,736 )
2024	2024	SANFORD RESEARCH	801 BROADWAY N	FARGO	ND	58102	CASS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/12/2024	NON-COMPETING CONTINUATION	$358,736
														Subtotal = $358,736

Issue Date FY: 2023 ( Subtotal = $377,330 )
2023	2023	SANFORD RESEARCH	2301 E 60TH ST N	SIOUX FALLS	SD	57104	MINNEHAHA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/1/2023	NON-COMPETING CONTINUATION	$377,330
2023	2022	SANFORD RESEARCH	2301 E 60TH ST N	SIOUX FALLS	SD	57104	MINNEHAHA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	10/17/2022	NEW	$0
														Subtotal = $377,330

Issue Date FY: 2022 ( Subtotal = $377,330 )
2022	2022	SANFORD RESEARCH	2301 E 60TH ST N	SIOUX FALLS	SD	57104	MINNEHAHA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/15/2022	NEW	$377,330
														Subtotal = $377,330

Grand Total All Awards = $1,113,396

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Uncovering cargo and cell type specific molecular mechanisms of renal tubular epithelial transport

Award Number: R01DK131020

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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