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Structure and Function of Complexes that Regulate Ciliary Motility

Award Number: R01GM083122
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: 09/28/2007
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Structure and Function of Complexes that Regulate Ciliary Motility - PROJECT SUMMARY The overall goal of the proposed research is to provide a better understanding of how cilia move by dissecting the structure and function of ciliary complexes that regulate dynein activity and ciliary motility. Cilia and flagella are conserved and ubiquitous microtubule-based organelles with important roles in cell locomotion, fluid transport, sensation, cell signaling, and development, which are critical processes for the survival and proper function of many eukaryotic cells and tissues. In humans, defects in the motility and assembly of cilia are responsible for numerous congenital diseases, such as primary ciliary dyskinesia, chronic respiratory disease, infertility, brain developmental defects, congenital heart disease, and randomization of the left-right body axis. Our previous studies of both inhibited and actively beating wild type and mutant cilia have opened a new window into the functional organization of motile cilia. However, long-standing fundamental questions remain, for example, about how regulatory signals change dynein’s activity on a molecular level, what are the roles of the different regulatory complexes during ciliary motility, and how dyneins are spatially and temporally coordinated to generate the oscillatory beating typical for cilia. Building on a strong premise of both published and preliminary data, this proposal directly addresses these critical open questions through three specific aims that are directed at (Aim 1) revealing the proteome and near-atomic resolution structure of the full-length radial spoke RS3 in mouse respiratory cilia, (Aim 2) understanding the functional roles of the regulatory ATPase domain of DRC11 – a nexin-dynein regulatory complex subunit – for proper regulation of ciliary motility, and (Aim 3) characterizing ciliary components that assemble only on specific doublets to ascertain if their inherently asymmetric distribution contributes to generating ciliary beating and/or different waveforms. We use a powerful and innovative combination of modern approaches, including a multi-scale imaging approach that combines near-atomic resolution cryo-EM single particle analysis, cryo-electron tomography to image mutant cilia and tagged proteins with molecular resolution, and expansion light microscopy to determine the doublet-specific distribution of specific ciliary proteins. We expect that our combined studies will provide important new conceptual and mechanistic insights into ciliary motility and regulation, which will also impact our understanding of ciliary diseases.


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 = $460,506 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	002	15	2/24/2025	NON-COMPETING CONTINUATION	$460,506
2025	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	14	2/12/2025	COMPETING CONTINUATION	$932
2025	2022	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	13	2/12/2025	NON-COMPETING CONTINUATION	-$932
														Subtotal = $460,506

Issue Date FY: 2024 ( Subtotal = $511,672 )
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	14	3/22/2024	COMPETING CONTINUATION	$511,672
														Subtotal = $511,672

Issue Date FY: 2022 ( Subtotal = $457,934 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	13	7/27/2022	NON-COMPETING CONTINUATION	$45,796
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	13	3/17/2022	NON-COMPETING CONTINUATION	$412,138
														Subtotal = $457,934

Issue Date FY: 2021 ( Subtotal = $457,934 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	12	3/10/2021	NON-COMPETING CONTINUATION	$457,934
														Subtotal = $457,934

Issue Date FY: 2020 ( Subtotal = $457,934 )
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	11	3/26/2020	NON-COMPETING CONTINUATION	$457,934
														Subtotal = $457,934

Issue Date FY: 2019 ( Subtotal = $457,934 )
2019	2019	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	10	3/29/2019	COMPETING CONTINUATION	$457,934
														Subtotal = $457,934

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2015	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Biomedical Research and Research Training	000	9	11/21/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $323,719 )
2015	2015	BRANDEIS UNIVERSITY	415 SO ST, 119 BERNSTEIN-MARCU	WALTHAM	MA	02254		USA	Biomedical Research and Research Training	000	9	8/11/2015	NON-COMPETING CONTINUATION	$323,719
														Subtotal = $323,719

Issue Date FY: 2014 ( Subtotal = $322,766 )
2014	2014	BRANDEIS UNIVERSITY	415 SO ST, 119 BERNSTEIN-MARCU	WALTHAM	MA	02254		USA	Biomedical Research and Research Training	000	8	9/4/2014	NON-COMPETING CONTINUATION	$322,766
														Subtotal = $322,766

Issue Date FY: 2013 ( Subtotal = $310,548 )
2013	2013	BRANDEIS UNIVERSITY	415 SO ST, 119 BERNSTEIN-MARCU	WALTHAM	MA	02453	MIDDLESEX	USA	Biomedical Research and Research Training	000	7	6/24/2013	NON-COMPETING CONTINUATION	$310,548
														Subtotal = $310,548

Issue Date FY: 2012 ( Subtotal = $322,000 )
2012	2012	BRANDEIS UNIVERSITY	415 SO ST, 119 BERNSTEIN-MARCU	WALTHAM	MA	02453	MIDDLESEX	USA	Biomedical Research and Research Training	000	6	8/13/2012	COMPETING CONTINUATION	$322,000
2012	2011	BRANDEIS UNIVERSITY	415 SO ST, 119 BERNSTEIN-MARCU	WALTHAM	MA	02254		USA	Biomedical Research and Research Training	001	5	8/13/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $322,000

Issue Date FY: 2011 ( Subtotal = $291,695 )
2011	2011	BRANDEIS UNIVERSITY	415 SO ST, 119 BERNSTEIN-MARCU	WALTHAM	MA	02453	MIDDLESEX	USA	Biomedical Research and Research Training	000	5	8/29/2011	NON-COMPETING CONTINUATION	$291,695
														Subtotal = $291,695

Issue Date FY: 2010 ( Subtotal = $341,079 )
2010	2010	BRANDEIS UNIVERSITY	415 SO ST, 119 BERNSTEIN-MARCU	WALTHAM	MA	02453	MIDDLESEX	USA	Biomedical Research and Research Training	000	3	3/8/2010	SUPPLEMENT FOR EXPANSION	$79,137
2010	2010	BRANDEIS UNIVERSITY	415 SO ST, 119 BERNSTEIN-MARCU	WALTHAM	MA	02453	MIDDLESEX	USA	Biomedical Research and Research Training	001	4	9/14/2010	NON-COMPETING CONTINUATION	$261,942
2010	2010	BRANDEIS UNIVERSITY	415 SO ST, 119 BERNSTEIN-MARCU	WALTHAM	MA	02254		USA	Biomedical Research and Research Training	002	3	9/20/2010	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $341,079

Issue Date FY: 2009 ( Subtotal = $357,965 )
2009	2009	BRANDEIS UNIVERSITY	415 SO ST, 119 BERNSTEIN-MARCU	WALTHAM	MA	02453	MIDDLESEX	USA	Biomedical Research and Research Training	000	3	9/4/2009	NON-COMPETING CONTINUATION	$298,620
2009	2009	BRANDEIS UNIVERSITY	415 SO ST, 119 BERNSTEIN-MARCU	WALTHAM	MA	02453	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	001	3	9/30/2009	SUPPLEMENT FOR EXPANSION	$59,345
														Subtotal = $357,965

Issue Date FY: 2008 ( Subtotal = $297,045 )
2008	2008	BRANDEIS UNIVERSITY	415 SO ST, 119 BERNSTEIN-MARCU	WALTHAM	MA	02254		USA	Biomedical Research and Research Training	000	2	8/29/2008	NON-COMPETING CONTINUATION	$297,045
														Subtotal = $297,045

Issue Date FY: 2007 ( Subtotal = $309,002 )
2007	2007	BRANDEIS UNIVERSITY	415 SO ST, 119 BERNSTEIN-MARCU	WALTHAM	MA	02254		USA	Biomedical Research and Research Training	000	1	9/20/2007	NEW	$309,002
														Subtotal = $309,002

Grand Total All Awards = $5,679,733

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Structure and Function of Complexes that Regulate Ciliary Motility

Award Number: R01GM083122

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: 09/28/2007

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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