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Decoding reno-protective mechanisms in mouse Pkhd1 models: Implications for ARPKD therapeutics

Award Number: R01DK121530
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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PROJECT SUMMARY There are ~1,500 patients in the United States with autosomal recessive polycystic kidney disease (ARPKD; MIM 173900), a hepatorenal fibrocystic disorder characterized by enlarged kidneys with innumerable collecting duct cysts and progressive loss of renal function. Essentially all cases of ARPKD can be attributed to mutations in PKHD1, which encodes a single-pass transmembrane protein, fibrocystin/polyductin (FPC). We currently have very little insight into the pathogenesis of human ARPKD and thus, treatment is largely supportive. Striking species-specific differences in the PKHD1/Pkhd1 renal phenotype may offer important insights into disease mechanisms. While human patients with either missense or truncating PKHD1 mutations have severe renal cystic disease, mouse Pkhd1 models with engineered truncating mutations (and presumably loss of FPC function) express minimal or no renal disease. Our preliminary studies reveal that while MYC is overexpressed in human ARPKD kidneys, Myc is not overexpressed in mouse Pkhd1 kidneys. In previous studies, we have shown that FPC undergoes Notch-like processing with cleavage of the carboxy terminus (FPC-CTD) from the plasma membrane and nuclear trafficking. Here, we demonstrate that the mouse FPC-CTD binds directly to the Myc P1 promoter and increases Myc expression. Based on these findings, we hypothesize that mouse renal epithelia can compensate for the loss of FPC-CTD function through reno-protective mechanisms and that species-specific, FPC-CTD regulation of Myc expression is central to this reno-protection. We speculate that while these mechanisms are not normally operative in human renal epithelia, they may identify new opportunities for therapeutic targeting in human ARPKD renal disease. We propose two specific aims to test our hypothesis: (1) define how the FPC-CTD regulates Myc/MYC expression in mouse and human renal epithelia and determine whether disruption of the proposed regulatory circuits is a central driver of renal cystogenesis; and (2) compare the FPC-CTD nuclear interactome in mouse and human renal epithelia and test whether differences in transcriptional targets identifies reno-protective pathways in mouse kidneys. Our studies will advance the field by sequentially addressing the transcriptional role of FPC-CTD. Specifically, we will: 1) determine mouse Pkhd1 models; how FPC-CTD related Myc transcriptional regulation contributes to reno-protection in and 2) identify putative mechanisms that allow mouse renal epithelia to compensate for the loss of FPC-CTD nuclear function. Moving forward, these data will lay the foundation for translating mouse reno-protective mechanisms into novel, therapeutic strategies that attenuate human PKHD1-related renal cystic disease.


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 = $376,992 )
2024	2024	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/20/2024	NON-COMPETING CONTINUATION	$376,992
														Subtotal = $376,992

Issue Date FY: 2023 ( Subtotal = $392,700 )
2023	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	6/15/2023	NON-COMPETING CONTINUATION	$0
2023	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	6/13/2023	NON-COMPETING CONTINUATION	$0
2023	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/30/2023	NON-COMPETING CONTINUATION	$392,700
														Subtotal = $392,700

Issue Date FY: 2022 ( Subtotal = $392,700 )
2022	2022	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/27/2022	NON-COMPETING CONTINUATION	$392,700
														Subtotal = $392,700

Issue Date FY: 2021 ( Subtotal = $392,700 )
2021	2021	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/2/2021	NON-COMPETING CONTINUATION	$392,700
														Subtotal = $392,700

Issue Date FY: 2020 ( Subtotal = $392,700 )
2020	2020	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/22/2020	NEW	$392,700
														Subtotal = $392,700

Grand Total All Awards = $1,947,792

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Decoding reno-protective mechanisms in mouse Pkhd1 models: Implications for ARPKD therapeutics

Award Number: R01DK121530

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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