Saturday, December 21, 2024 12/21/2024

Human-specific Abnormal Alternative Splicing of the Wild-type PKD1 Gene Induces Premature Termination of Polycystin-1

Award Number: R01DK122205
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 two major theories concerning the pathogenesis of ADPKD; the first and most accepted is that an individual is born with a defective allele and then the normal WT allele undergoes a somatic mutation that gives rise first to a tubular dilation and then a cyst, the `two hit' hypothesis. The second idea is that gene dosage is enough to cause disease, the level of the protein product of the PKD1 gene, polycystin-1 (PC1) decreases below a threshold and cysts appear in a stochastic manner. We wish to investigate these two ideas in a novel manner using the fact that PC1, PC2 and fibrocystin are all present on an exosome we term the exosome-like vesicle (ELV). We know that the level of PC1 is decreased in individuals with PKD1 mutations and that the amount of PC1 per ELV is inversely proportional to height adjust total kidney volume (HtTKV). Observing the total amount of PC1 in pooled exosomes tells us little about the pathogenesis of the disease. However, a new technology has become available which allows an investigator to determine the amount of PC1 on individual ELVs, NanoView. We know that ELVs contain CD133 (prominin) which colocalizes on exosomes with PC1. We predict that if the `two hit' hypothesis is true, then clones of PKD1 null cells in the kidney will produce ELVs that are CD133+ and PC1- and that the NanoView will see a bimodal distribution of PC1+ ELVs in ADPKD but not in normal urine. The ratio of CD133+/PC- to CD133+/PC1+ ELVs will correlate with HtTKV. If haploinsufficiency is the mechanism, then the mean intensity of PC1 per ELV will be inversely proportional to HtTKV. Thus, NanoView technology can distinguish between the `two hit' and haploinsufficiency models. To further dissect the mechanism of haploinsufficiency we will investigate two major ideas. The first is that the human PKD1 gene is unusual in that it has two long CT rich tracts in introns 21 and 22 which interfere with splicing and generate a smaller form of PC1, we term Trunc_PC1. We will investigate the possibility that splicing efficiency correlates inversely with HtTKV. The second idea is that there is person to person variation in PKD1 promoter strength and that the promoter attenuates with age. We will investigate this possibility using real time RT-PCR. We think that the different mechanisms have a profound effect on the way the disease may be treated. If haploinsufficiency is correct, then strategies designed to increase the amount of endogenous PKD1 mRNA and PC1 protein will be appropriate whereas in the `two hit' scenario these strategies will not work and may be deleterious as both alleles are defective.


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 = $323,136 )
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	8/9/2024	NON-COMPETING CONTINUATION	$323,136
														Subtotal = $323,136

Issue Date FY: 2023 ( Subtotal = $336,600 )
2023	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/27/2023	NON-COMPETING CONTINUATION	$336,600
														Subtotal = $336,600

Issue Date FY: 2022 ( Subtotal = $336,600 )
2022	2022	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/10/2022	NON-COMPETING CONTINUATION	$336,600
														Subtotal = $336,600

Issue Date FY: 2021 ( Subtotal = $336,600 )
2021	2021	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/12/2021	NON-COMPETING CONTINUATION	$336,600
														Subtotal = $336,600

Issue Date FY: 2020 ( Subtotal = $336,600 )
2020	2020	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/15/2020	NEW	$336,600
														Subtotal = $336,600

Grand Total All Awards = $1,669,536

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Human-specific Abnormal Alternative Splicing of the Wild-type PKD1 Gene Induces Premature Termination of Polycystin-1

Award Number: R01DK122205

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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