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Hedgehog signaling at the cell's antenna: Smoothened and the primary cilium

Award Number: R01AR054396
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2007
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Hedgehog signaling at the cell's antenna: Smoothened and the primary cilium - ABSTRACT Hedgehog signaling is a means of intercellular communication that, in vertebrates, relies on immotile cellular appendages called primary cilia. In the skin, Hedgehog signaling is critical for development, homeostasis, and repair, regulating hair follicle formation, sebaceous gland development, and epidermal regeneration. In our previous work, we discovered that vertebrate Smoothened, a central component of the Hedgehog signal transduction pathway, functions in primary cilia, including in the skin. We also found that certain cancers critically depend on their cilia, that the ciliary membrane has a unique lipid composition critical for Hedgehog signaling, and that cyclic AMP (cAMP) generated inside cilia conveys different information than cAMP generated outside cilia. Despite these insights into ciliary signaling, how the Hedgehog pathway is transduced downstream of Smoothened has remained unclear. In this renewal application, we seek to build on our recent advances to determine how ciliary and cytoplasmic pools of cAMP communicate different information (Aim 1). Also, we will elucidate the molecular mechanisms by which Smoothened regulates ciliary protein kinase A (PKA) to activate the transcriptional effector GLI2 (Aim 2). And we will determine how the HH pathway transcription factor GLI2 executes its transcriptional program in mammalian development (Aim 3). The proposed experiments leverage a combination of chemogenetics, phosphoproteomics, mouse genetics, cell biology, super-resolution imaging, and genomics (including CUT&RUN). Execution of this project will advance mechanistic understanding of HH signaling, redefine models of cAMP compartmentalization, and provide insights into ciliopathies and congenital disorders. We focus on ciliary Hedgehog signaling in development, but the tools and discoveries arising from this project are likely to inform our understanding of ciliopathies, the function of Hedgehog signaling in adult physiology, and the biology of ciliary GPCR signaling. Thus, this project will not only enhance our knowledge of vertebrate development, but also uncover fundamental principles of subcellular signal transduction that may illuminate other signaling pathways.


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 = $2,033,477 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	18	5/15/2026	COMPETING CONTINUATION	$2,033,477
2026	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	17	2/19/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,033,477

Issue Date FY: 2024 ( Subtotal = $450,962 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	17	6/25/2024	NON-COMPETING CONTINUATION	$450,962
														Subtotal = $450,962

Issue Date FY: 2023 ( Subtotal = $474,290 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	16	6/29/2023	NON-COMPETING CONTINUATION	$474,290
														Subtotal = $474,290

Issue Date FY: 2022 ( Subtotal = $478,410 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	6/29/2022	NON-COMPETING CONTINUATION	$478,410
														Subtotal = $478,410

Issue Date FY: 2021 ( Subtotal = $477,292 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	14	6/24/2021	NON-COMPETING CONTINUATION	$477,292
2021	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	12	11/9/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $477,292

Issue Date FY: 2020 ( Subtotal = $500,582 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	13	6/7/2020	COMPETING CONTINUATION	$500,582
														Subtotal = $500,582

Issue Date FY: 2019 ( Subtotal = $456,339 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	12	6/13/2019	NON-COMPETING CONTINUATION	$456,339
														Subtotal = $456,339

Issue Date FY: 2018 ( Subtotal = $462,313 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	6/20/2018	NON-COMPETING CONTINUATION	$462,313
														Subtotal = $462,313

Issue Date FY: 2017 ( Subtotal = $468,302 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	6/30/2017	NON-COMPETING CONTINUATION	$468,302
														Subtotal = $468,302

Issue Date FY: 2016 ( Subtotal = $474,176 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	6/21/2016	NON-COMPETING CONTINUATION	$474,176
														Subtotal = $474,176

Issue Date FY: 2015 ( Subtotal = $479,727 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	5/15/2015	COMPETING CONTINUATION	$479,727
														Subtotal = $479,727

Issue Date FY: 2013 ( Subtotal = $293,915 )
2013	2013	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	7/17/2013	NON-COMPETING CONTINUATION	$293,915
														Subtotal = $293,915

Issue Date FY: 2012 ( Subtotal = $309,385 )
2012	2012	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	6/28/2012	NON-COMPETING CONTINUATION	$309,385
														Subtotal = $309,385

Issue Date FY: 2011 ( Subtotal = $309,385 )
2011	2011	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	6/23/2011	NON-COMPETING CONTINUATION	$309,385
														Subtotal = $309,385

Issue Date FY: 2010 ( Subtotal = $322,276 )
2010	2010	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	6/18/2010	NON-COMPETING CONTINUATION	$322,276
														Subtotal = $322,276

Issue Date FY: 2009 ( Subtotal = $325,532 )
2009	2009	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	7/29/2009	NON-COMPETING CONTINUATION	$0
2009	2009	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/22/2009	NON-COMPETING CONTINUATION	$325,532
														Subtotal = $325,532

Issue Date FY: 2008 ( Subtotal = $325,532 )
2008	2008	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/28/2008	NON-COMPETING CONTINUATION	$325,532
														Subtotal = $325,532

Issue Date FY: 2007 ( Subtotal = $331,100 )
2007	2007	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/13/2007	NEW	$331,100
														Subtotal = $331,100

Grand Total All Awards = $8,972,995

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Hedgehog signaling at the cell's antenna: Smoothened and the primary cilium

Award Number: R01AR054396

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2007

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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