Tuesday, July 1, 2025 7/1/2025

Mechanisms of Smoothened Activation in Hedgehog Signaling

Award Number: R01GM138992
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2025

Group Awards By:

View Award Description

Mechanisms of Smoothened Activation in Hedgehog Signaling - PROJECT SUMMARY/ABSTRACT MECHANISMS OF SMOOTHENED ACTIVATION IN HEDGEHOG SIGNALING. The Hedgehog (Hh) signaling pathway coordinates development in humans and most metazoans. In adult tissues, aberrant Hh pathway activation drives various cancers, including basal cell carcinoma of the skin and pediatric brain medulloblastoma. An unusual mechanism enables Hh signal transduction. In the basal state, the transporter- like molecule Patched1 (PTCH1) represses Smoothened (SMO), a seven-transmembrane protein. Hh inhibits PTCH1, which unleashes SMO activity causing downstream transcription. A leading mechanistic hypothesis is that cellular sterols activate SMO, but are sequestered by PTCH1 in the absence of Hh. Connecting the putative transport function of PTCH1 to SMO activation remains one of the central mysteries in understanding how the Hh signal is transduced across the membrane. A critical gap is how, and which, sterols directly influence SMO activation. This proposal will address these questions in two aims. The first aim focuses on which sterols activate SMO. Here, we will combine biochemistry, structural biology, and signaling studies to define which sterols can activate SMO and how they do so. In the second aim, we focus on how sterol binding to distinct sites on SMO influences Hh pathway activity. We will use X-ray crystallography, cryo-electron microscopy, and NMR spectroscopy to generate an integrated high-resolution perspective on where sterols bind to SMO, and how they influence SMO activity. These studies will provide a mechanistic picture on how the Hh signal is transduced across the membrane. Such insights may enable the design of SMO inhibitors less susceptible to tumor resistance or Hh pathway modulators for regenerative medicine.


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 = $286,837 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	4	11/22/2024	NON-COMPETING CONTINUATION	$286,837
														Subtotal = $286,837

Issue Date FY: 2024 ( Subtotal = $319,064 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Biomedical Research and Research Training	001	3	6/18/2024	NON-COMPETING CONTINUATION	$31,906
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	3	11/3/2023	NON-COMPETING CONTINUATION	$287,158
														Subtotal = $319,064

Issue Date FY: 2023 ( Subtotal = $323,020 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	2	11/10/2022	NON-COMPETING CONTINUATION	$290,718
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Biomedical Research and Research Training	001	2	3/30/2023	NON-COMPETING CONTINUATION	$32,302
														Subtotal = $323,020

Issue Date FY: 2022 ( Subtotal = $331,512 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Biomedical Research and Research Training	000	1	1/19/2022	NEW	$331,512
														Subtotal = $331,512

Grand Total All Awards = $1,260,433

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Mechanisms of Smoothened Activation in Hedgehog Signaling

Award Number: R01GM138992

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer