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Regulation of GLIS3, a Ciliary Transcription Factor that Prevents Kidney Cysts

Award Number: K08DK143339
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/15/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Regulation of GLIS3, a Ciliary Transcription Factor that Prevents Kidney Cysts - ABSTRACT/PROJECT SUMMARY This application presents a five-year mentored research and training plan that will prepare Dr. Gabriel Loeb to lead a successful independent academic research program focused on the mechanisms underlying ciliary kidney diseases. Dr. Loeb completed his MD and PhD at the Tri-Institutional MD-PhD Program at Weill Cornell Medical College/Rockefeller University/Memorial Sloan Kettering where he studied the function of microRNAs in the lab of Dr. Alexander Rudensky. Dr. Loeb completed his fellowship in Nephrology at UCSF and his long- term career goal is to advance our understanding of the mechanisms underlying genetic forms of kidney disease, particularly those caused by mutations in proteins that localize to primary cilia including Autosomal Dominant Polycystic Kidney Disease and Nephronophthisis. This project will lay the foundation for his independent research program, by dissecting ciliary pathways involved in kidney cystogenesis. Mutation in either of two ciliary membrane proteins, PKD1 and PKD2, is responsible for most Autosomal Dominant Polycystic Kidney Disease. However, the effectors of PKD1/PKD2 signaling remain unknown. GLIS3 is a transcription factor that localizes to primary cilia and the cell nucleus. Loss of GLIS3 phenocopies the severe cystogenesis caused by loss of PKD1 or PKD2. These data suggest the hypothesis that GLIS3 is a long-sought effector of ciliary PKD1/PKD2 signaling. This hypothesis is tested in two independent aims by 1) testing whether GLIS3 is regulated by Polycystins and acts downstream of Polycystins to prevent cystogenesis and 2) testing whether GLIS3 traffics from primary cilia to the nucleus and is regulated by ciliary signaling mediators. This work will employing innovative approaches to study ciliary signaling to generate fundamental knowledge about the pathways underlying cystic kidney disease. The proposed career development plan includes training to help establish Dr. Loeb’s ability to dissect pathways involved in genetic forms of kidney disease using mouse models, organoid models, and advanced imaging. In addition, the training plan will help Dr. Loeb develop all the non-experimental skills necessary for a career as a successful independent academic investigator. These additional skills include laboratory leadership, trainee mentoring and supervision, and grant writing. Dr. Loeb has assembled a world-class mentorship team with complementary expertise in mouse models and ciliary signaling (Primary mentor, Dr. Jeremy Reiter), imaging and ciliary ion channels (Co-mentor Dr. Markus Delling), organoids and kidney disease models (Advisory Committee Member Dr. Andrew McMahon), Ciliary biochemistry and protein analysis (Advisory Committee Member Dr. Maxence Nachury), Polycystic Kidney Disease (Advisory Committee Member Dr. Meyeon Park), and human genetics and single-cell genomics (Dr. David Erle). Dr. Loeb, his mentors, and the Department of Medicine at UCSF are fully committed to this proposal and to his goal of becoming an independent scientist-nephrologist by the completion of this training period.


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 = $174,744 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/25/2026	NON-COMPETING CONTINUATION	$174,744
														Subtotal = $174,744

Issue Date FY: 2025 ( Subtotal = $176,244 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/5/2025	NEW	$176,244
														Subtotal = $176,244

Grand Total All Awards = $350,988

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Regulation of GLIS3, a Ciliary Transcription Factor that Prevents Kidney Cysts

Award Number: K08DK143339

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/15/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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