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The Role of E3-Ubiquitin Ligase Complex in Genitourinary Tract Development and Function

Award Number: R01HD100985
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/02/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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The Role of E3-Ubiquitin Ligase Complex in Genitourinary Tract Development and Function - Summary: Despite their high prevalence, the molecular basis for common genitourinary (GU) congenital defects is poorly understood. We have identified and validated gene lesions at the KCTD13/16p11.2 locus as responsible for lower GU tract abnormalities, particularly cryptorchidism and hypospadias. KCTD13 encodes a substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex, which regulates the actin cytoskeleton and cell migration via ubiquitination and degradation of RHOA. Notably, RHOA has been implicated in the maintenance of Sertoli-germ cell junctions to promote gametogenesis and gonads development. E3 ubiquitin ligases also regulate the androgen receptor (AR), which is key to male genitalia development and differentiation. We found that KCTD13 is robustly expressed in the GU tract and have recently shown that in comparison to normal controls, gene copy number variants are remarkably common in patients with GU birth defects. Moreover, we obtained in vitro and in vivo evidence that KCTD13 loss affects AR levels in testis and penis. We also observed that haploinsufficient and Kctd13 deficient mice had significantly higher incidence of cryptorchidism and decreased size of testes, seminal vesicles and penis size in conjunction with spermatogenic defects, causing severe subfertility. Further, Kctd13 null mice revealed a significant decrease in masculinization factor SOX9 levels and concomitant upregulation of the feminization factor RHOA. While our collective data suggest a key role of KCTD13 in male GU development, the mechanisms of how this molecule impinges upon the AR and/or SOX9 axes remain a major gap of knowledge. We hypothesize that gene dosage changes in KCTD13 alter the signaling of the masculinization axes, leading to abnormal GU tract development, defective gonad formation, undervirilization, and subfertility. In line with our reasoning, we will test two plausible independent mechanisms by which KCTD13 mediates lower GU tract development and differentiation. First, we hypothesize and test that gene dosage changes in KCTD13 affect GU tract development by affecting AR degradation, subcellular localization and downstream gene targets (AIM 1). Second, we hypothesize and test that KCTD13 affects the expression of masculinization factor SOX9 directly by modulating SOX9 ubiquitination or indirectly by regulating RHOA degradation, which in turn leads to defects in testis and penile development and differentiation (AIM 2). Finally, we identify and characterize the mutations in KCTD13- CUL3 pathway that are critical in GU development such that they could be used to generate a diagnostic kit for patients with disorders of sexual development (AIM3). Completion of the studies in this proposal will advance our understanding of the molecular mechanisms that underlie common GU birth defects.


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 = $304,829 )
2024	2024	THE NEMOURS FOUNDATION	6535 NEMOURS PKWY	ORLANDO	FL	32827	ORANGE	USA	Child Health and Human Development Extramural Research	002	6	5/7/2024	NON-COMPETING CONTINUATION	$27,713
2024	2024	THE NEMOURS FOUNDATION	6535 NEMOURS PKWY	ORLANDO	FL	32827	ORANGE	USA	Child Health and Human Development Extramural Research	001	6	2/22/2024	NON-COMPETING CONTINUATION	$277,116
2024	2023	THE NEMOURS FOUNDATION	6535 NEMOURS PKWY	ORLANDO	FL	32827	ORANGE	USA	Child Health and Human Development Extramural Research	000	5	2/8/2024	NON-COMPETING CONTINUATION	$0
2024	2022	THE NEMOURS FOUNDATION	6535 NEMOURS PKWY	ORLANDO	FL	32827	ORANGE	USA	Child Health and Human Development Extramural Research	004	4	8/20/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$194,869
2024	2022	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	003	3	8/20/2024	NON-COMPETING CONTINUATION	-$194,869
														Subtotal = $304,829

Issue Date FY: 2023 ( Subtotal = $307,907 )
2023	2023	THE NEMOURS FOUNDATION	6535 NEMOURS PKWY	ORLANDO	FL	32827	ORANGE	USA	Child Health and Human Development Extramural Research	003	5	5/12/2023	NON-COMPETING CONTINUATION	$307,907
2023	2022	THE NEMOURS FOUNDATION	6535 NEMOURS PKWY	ORLANDO	FL	32827	ORANGE	USA	Child Health and Human Development Extramural Research	002	4	5/11/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2022	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	000	3	10/21/2022	NON-COMPETING CONTINUATION	-$136,612
2023	2022	NEMOURS FOUNDATION, THE	6535 NEMOURS PKWY	ORLANDO	FL	32827	ORANGE	USA	Child Health and Human Development Extramural Research	001	4	10/21/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$136,612
														Subtotal = $307,907

Issue Date FY: 2022 ( Subtotal = $343,256 )
2022	2022	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	001	3	4/19/2022	NON-COMPETING CONTINUATION	$34,326
2022	2022	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	000	3	2/2/2022	NON-COMPETING CONTINUATION	$308,930
														Subtotal = $343,256

Issue Date FY: 2021 ( Subtotal = $343,256 )
2021	2021	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	000	2	2/11/2021	NON-COMPETING CONTINUATION	$343,256
														Subtotal = $343,256

Issue Date FY: 2020 ( Subtotal = $350,262 )
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	000	1	3/25/2020	NEW	$350,262
														Subtotal = $350,262

Grand Total All Awards = $1,649,510

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The Role of E3-Ubiquitin Ligase Complex in Genitourinary Tract Development and Function

Award Number: R01HD100985

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/02/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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