Tuesday, July 1, 2025 7/1/2025

Regulation of Hedgehog Signaling by new cilium proteins

Award Number: R15CA235749
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Regulation of Hedgehog Signaling by new cilium proteins - PROJECT SUMMARY Hedgehog (Hh) signaling is widely involved in development and cancers, including medulloblastoma (MB), the malignant pediatric brain tumor. Current treatment regimens bring life-long devastating side effects to survivors, generating a huge burden to the patients’ family. The current Hh pathway inhibitors are challenged by drug resistance and tumor relapse. We aim to understand the basic transduction mechanisms of the Hh pathway in order to provide new clues to treat Hh-related cancers. This proposal is based on my previous discovery that PDE4D controls local PKA activity at specific subcellular sites to regulate Hh signaling. In the past two years of this grant, we have studied the control of Hh signaling by local PDE4D-PKA at the centrosome. We found that 1) PDE4D3 is anchored to the centrosome by myomegalin to locally inhibit PKA activity, 2) knocking out myomegalin with shRNA or CRISPR/Cas9 specifically increases PKA activity at the centrosome, and 3) this selectively inhibits Hh signaling without interfering other PKA-related cellular events. Based on the exciting results and the innovative tools we have built, in the current proposal we will expand our research to systemically investigate the regulation of Hh signaling by local PKA in the cilium. We will 1) define the signaling mechanism from Smo to PKA in the cilium, a mysterious step in the Hh pathway; 2) determine the effects of selectively promoting ciliary PKA on Hh signaling and Hh-related tumor growth; and 3) identify the signaling transducers associated with Smo via proximity labeling-based proteomics to thoroughly illuminate its downstream signaling cascade during Hh transduction. Our approach is innovative because it combines cutting edge techniques to elucidate the long-standing questions in the Hh pathway. Its significance is underlined by the expectation that it will highlight new approaches to treat pediatric brain tumor with fewer side effects. Equally importantly, this research funding will allow me to engage first generation college students in biomedical research at UC Merced to diversify and strengthen academic research in the economically deprived California Central valley.


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 = -$3 )
2025	2022	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Cancer Biology Research	000	2	6/12/2025	COMPETING CONTINUATION	-$3
														Subtotal = -$3

Issue Date FY: 2024 ( Subtotal = -$113,416 )
2024	2022	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Cancer Biology Research	000	2	1/23/2024	COMPETING CONTINUATION	-$113,416
														Subtotal = -$113,416

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2019	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Cancer Biology Research	000	1	6/20/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $477,928 )
2022	2022	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95344	MERCED	USA	Cancer Biology Research	000	2	2/22/2022	COMPETING CONTINUATION	$443,028
2022	2022	UNIVERSITY OF CALIFORNIA MERCED	5200 N LAKE RD	MERCED	CA	95343	MERCED	USA	Cancer Biology Research	001	2	7/21/2022	COMPETING CONTINUATION	$34,900
														Subtotal = $477,928

Issue Date FY: 2019 ( Subtotal = $430,288 )
2019	2019	UNIVERSITY OF CALIFORNIA, MERCED	5200 N LAKE RD	MERCED	CA	95344	MERCED	USA	Cancer Biology Research	000	1	1/24/2019	NEW	$430,288
														Subtotal = $430,288

Grand Total All Awards = $794,797

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Regulation of Hedgehog Signaling by new cilium proteins

Award Number: R15CA235749

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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