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Discovery and pathogenic characterization of novel monogenic causes of bladder dysfunction

Award Number: K08DK127011
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Discovery and pathogenic characterization of novel monogenic causes of bladder dysfunction - PROJECT SUMMARY Title: Discovery and pathogenic characterization of novel monogenic causes of bladder dysfunction Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in childhood. Over 40 monogenic etiologies of CAKUT have been identified, and another 150 genes have been described to cause syndromes in which urinary tract malformations are an integral component. However, the majority of these genes coalesce into pathways that regulate upper urinary tract development, such as metanephric mesenchyme transition and ureteric bud formation. The pathogenesis and genetic regulation of lower urinary tract disease remain poorly understood. Recently, through the use of whole exome sequencing, I identified mutations in the α3-subunit of the nicotinic acetylcholine receptor, CHRNA3, as a novel cause of bladder dysfunction with secondary CAKUT. This is one of just eight known monogenic causes of congenital bladder dysfunction, and, uniquely, is a gene that regulates autonomic nervous system function. I hypothesize that additional monogenic causes of lower urinary tract disease can be identified through the use of whole exome sequencing, and additionally, that these genes will coalesce upon pathways that regulate urothelial signaling, detrusor contraction, and bladder innervation. The aims of the proposed research are twofold: (1) to apply both a candidate gene and unbiased analysis strategy to whole exome sequencing data in order to discover novel monogenic causes of bladder dysfunction and (2) to apply an integrated genomic approach using whole exome and whole transcriptome sequencing to an international cohort of children with CAKUT. Accomplishment of the proposed research above will provide additional insight into the pathomechanisms that govern bladder development and function, and, ultimately, could lead to novel therapeutic strategies for children with bladder dysfunction. In addition, validation of a method for urinary transcriptome sequencing can help to overcome current limitations in whole exome sequencing in the identification and interpretation of splice-altering genetic variants. This K08 application encompasses a comprehensive career development plan to not only ensure progress and success in carrying out the proposed research, but also to facilitate my transition to an independent investigator. It encompasses regular meetings with my mentor and advisory committee, research and career development seminars, courses in genomics and transcriptomics, and participation at national and international conferences. The research will be conducted in the rich academic environment at Boston Children's Hospital and Harvard Medical School, which provides an ideal environment for further training and career 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: 2025 ( Subtotal = $152,456 )
2025	2025	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	6/3/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$152,456
2025	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $152,456

Issue Date FY: 2024 ( Subtotal = $167,940 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/30/2024	NON-COMPETING CONTINUATION	$167,940
														Subtotal = $167,940

Issue Date FY: 2023 ( Subtotal = $167,940 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/15/2023	NON-COMPETING CONTINUATION	$167,940
														Subtotal = $167,940

Issue Date FY: 2022 ( Subtotal = $167,940 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/13/2022	NON-COMPETING CONTINUATION	$167,940
														Subtotal = $167,940

Issue Date FY: 2021 ( Subtotal = $169,440 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/1/2021	NEW	$169,440
														Subtotal = $169,440

Grand Total All Awards = $825,716

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Discovery and pathogenic characterization of novel monogenic causes of bladder dysfunction

Award Number: K08DK127011

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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