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Polycystin-1 C terminal tail cleavage: Mechanisms and meaning

Award Number: R01DK139319
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2025
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Polycystin-1 C terminal tail cleavage: Mechanisms and meaning - Summary Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common potentially lethal genetic disorders, affecting ~1:1,000 people and producing end stage renal disease in 50% of affected individuals. The disease is characterized by the formation of nephron- derived fluid-filled cysts, whose initiation and expansion compromises the structure and function of the remaining renal parenchyma. ADPKD is caused by mutations in either of two genes, Pkd1 and Pkd2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC1 is an extremely large membrane protein comprised of 4,302 amino acids that spans the bilayer 11 times. PC2 spans the membrane 6 times and is a member of the Trp family of non-selective cation channels. PC1 and PC2 interact with one another to form a complex that localizes to a number of subcellular compartments, including the primary cilium and the mitochondrion-associated membrane domains of the endoplasmic reticulum. More than two decades after their discovery, the principal physiological functions of these proteins and the processes through which their dysfunction leads to cystic disease remain largely unknown. PC1 undergoes cleavages within its N and C-terminal domains. C-terminal cleavage produces fragments that translocate to mitochondria and to nuclei. We have found that transgenic expression of a protein corresponding to the final 200 amino acid residues of PC1 (P200) in orthologous murine models of ADPKD suppresses the cystic phenotype and preserves renal function. This suppression depends upon an interaction between the C-terminal tail of PC1 and the mitochondrial enzyme Nicotinamide Nucleotide Transhydrogenase (NNT). The discovery that a short fragment of PC1 reduces disease severity in mouse models of ADPKD raises a number of exciting questions that will be pursued in our proposed studies. To explore these questions we will 1) determine whether P200 expression suppresses cyst formation and reverses established cystic disease in multiple mouse models of ADPKD; 2) determine how P200 affects mitochondrial function and cellular energy metabolism; and 3) determine how PC1 C terminal tail fragments are produced in vivo and how they affect metabolism and pathways involved in cyst formation. Addressing these questions will provide important insights into the normal physiological functions of PC1 and will suggest new potential targets for therapeutic development.


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 = $640,797 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/12/2025	NON-COMPETING CONTINUATION	$640,797
														Subtotal = $640,797

Issue Date FY: 2025 ( Subtotal = $640,001 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/19/2024	NEW	$640,001
														Subtotal = $640,001

Grand Total All Awards = $1,280,798

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Polycystin-1 C terminal tail cleavage: Mechanisms and meaning

Award Number: R01DK139319

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2025

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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