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Signaling Mechanisms and Cellular Functions of a Ciliopathy-Associated Protein Kinase

Award Number: R01GM127690
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: 05/01/2018
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Signaling Mechanisms and Cellular Functions of a Ciliopathy-Associated Protein Kinase - Project Summary Ciliopathies comprise an expanding group of human disorders associated with genetic mutations causing cilia dysfunction. Cilia can be divided into motile and non-motile (primary) forms. The primary cilium is a microtubule (MT)-based organelle that protrudes from the apical surface of nearly every mammalian cell and plays a critical role in chemical sensation, signal transduction, and control of various cellular functions. To date, there are still major gaps in our knowledge about the dynamic structure and function of the primary cilium, and the underlying molecular basis of ciliopathies. Our research proposal is focused on elucidating the molecular mechanism by which pathogenic mutations in the human CILK1 (ciliogenesis associated kinase 1) gene cause ciliopathies. CILK1 encodes a serine/threonine protein kinase that negatively regulates cilia length and ciliogenesis. Three significant questions about CILK1 remain to be addressed. First, what is the identify of CILK1 substrates that relate to its ciliopathy phenotype? Our data challenged the current view that MT- associated motor KIF3A is the CILK1 substrate responsible for the ciliopathy phenotype by showing that disrupting CILK1 phosphorylation of KIF3A in vivo did not reproduce CILK1 mutant phenotype. In this continuation project, we hypothesize that CILK1 suppresses ciliogenesis by phosphorylating a novel MT- associated ciliary protein and promoting MT disassembly. Second, how is CILK1 activity regulated in the primary cilium? CILK1 requires phosphorylation of its MAPK-like TDY motif for full activation, but growth factors have little stimulatory effect on its activity. Our new preliminary data shows that reducing intracellular cAMP stimulates CILK1. We hypothesize that CILK1 activity is negatively regulated by ciliary cAMP-dependent phosphorylation. Third, how CILK1 human disease variants impact cilia function and signaling and tissue development? We observed human disease variants in the non-catalytic C-terminal domain (CTD) of CILK1 that retain CILK1 catalytic activity but produce a loss-of-function effect on suppression of ciliogenesis. We hypothesize that CILK1 variants in the CTD perturb CILK1 localization and substrate recognition, thereby compromising its ability to suppress ciliogenesis. We propose three specific aims to test these hypotheses. Aim 1 will determine how CILK1 signals through a novel signaling pathway to control cilia length and ciliogenesis. Aim 2 will determine how cAMP inhibits CILK1 to elongate cilia and promote ciliogenesis. Aim 3 will determine the impact of CILK1 pathogenic variants on substrate phosphorylation, cilia function, Hedgehog signaling, and tissue development. The significance of this project derives from human ciliopathies that have an expanding disease spectrum with devastating clinical outcomes. Our studies are innovative in using novel genetically engineered animal and cell models to elucidate new mechanisms that control cilia function and signaling. Our research will exert strong impact on basic knowledge about the primary cilium and significantly advance our understanding of the disease mechanisms underlying human ciliopathies.


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 = $332,690 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	001	6	6/25/2024	NON-COMPETING CONTINUATION	$33,269
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	6	2/8/2024	NON-COMPETING CONTINUATION	$299,421
														Subtotal = $332,690

Issue Date FY: 2023 ( Subtotal = $363,997 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	001	5	2/20/2023	NON-COMPETING CONTINUATION	$33,269
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	002	5	5/25/2023	SUPPLEMENT FOR EXPANSION	$31,307
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	5	2/3/2023	NON-COMPETING CONTINUATION	$299,421
														Subtotal = $363,997

Issue Date FY: 2022 ( Subtotal = $332,690 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	4	2/11/2022	NON-COMPETING CONTINUATION	$299,421
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	001	4	7/27/2022	NON-COMPETING CONTINUATION	$33,269
														Subtotal = $332,690

Issue Date FY: 2021 ( Subtotal = $332,690 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	002	3	9/4/2021	COMPETING CONTINUATION	$17
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	3	4/27/2021	COMPETING CONTINUATION	$332,690
2021	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	001	2	9/4/2021	NON-COMPETING CONTINUATION	-$17
														Subtotal = $332,690

Issue Date FY: 2019 ( Subtotal = $323,000 )
2019	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	2	4/11/2019	NON-COMPETING CONTINUATION	$323,000
														Subtotal = $323,000

Issue Date FY: 2018 ( Subtotal = $322,833 )
2018	2018	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Biomedical Research and Research Training	000	1	4/27/2018	NEW	$322,833
														Subtotal = $322,833

Grand Total All Awards = $2,007,900

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Signaling Mechanisms and Cellular Functions of a Ciliopathy-Associated Protein Kinase

Award Number: R01GM127690

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: 05/01/2018

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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