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The role of copines in the regulation of the actin cytoskeleton and membrane trafficking

Award Number: R15GM078089
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: 07/01/2008
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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The role of copines in the regulation of the actin cytoskeleton and membrane trafficking - PROJECT SUMMARY Copines are a family of calcium-dependent membrane binding proteins found in most eukaryotic organisms including humans, which have nine different copine genes. Copines have been implicated in numerous human cancers. However, at this time there is no unifying theme with respect to the function of these elusive proteins. The main goal of this research project is to determine whether a common basic mechanistic function can be attributed to all copine proteins. We have been using the model organism Dictyostelium discoideum to study these enigmatic proteins. Dictyostelium is a good model organism to study these proteins because they have six copines genes, while other model organisms either have a few or no copine genes. Our studies have mostly focused on Copine A (CpnA). However, we now have many of the tools to study the other five copines (CpnB-F). Our studies on cpnA knockout mutants in Dictyostelium indicate that CpnA is involved in many cellular functions including processes that require the actin cytoskeleton (i.e. cytokinesis, chemotaxis, cell polarity, and adhesion) and require membrane fusion (i.e. contractile vacuole expulsion, and postlysosome maturation and exocytosis). Biochemical studies indicate that CpnA binds to acidic phospholipids and actin filaments in a calcium-dependent manner. Localization studies indicate that CpnA is a soluble cytoplasmic protein that translocates to the plasma membrane and the membranes of the contractile vacuole system and organelles of the endolysosomal system in response to a rise in calcium concentration. Two main hypotheses for the function of CpnA emerge from our studies: CpnA functions in the calcium-dependent regulation of 1) actin filament dynamics and/or 2) membrane fusion. Therefore, we propose to use Dictyostelium to explore the idea that all copines, from single-celled organisms to humans, are involved in the calcium-dependent regulation of actin filament dynamics and/or membrane fusion. We plan to use several strategies that include the functional characterization of copine knockout mutants, identification of copine protein binding partners, and fluorescence microscopy techniques to visualize actin filament dynamics and membrane fusion in the copine knockout mutants. We will also explore the more specific hypothesis that copines regulate actin filaments on membrane surfaces to regulate membrane fusion. If we find that not all copines function in the regulation of actin filament dynamics and/or membrane fusion, a unifying theme for copines will most likely emerge as we characterize each of the copine knockout mutants to identify any common defects and identify common binding-partners of copine proteins. This new knowledge can be then be used to understand the molecular mechanisms underlying many of the human cancers in which copines are highly expressed.


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 = -$1,891 )
2025	2021	CENTRAL MICHIGAN UNIVERSITY	119 BOVEE UNIVERSITY CTR	MOUNT PLEASANT	MI	48858	ISABELLA	USA	Biomedical Research and Research Training	000	3	8/19/2025	COMPETING CONTINUATION	-$1,891
														Subtotal = -$1,891

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	CENTRAL MICHIGAN UNIVERSITY	119 BOVEE UNIVERSITY CTR	MOUNT PLEASANT	MI	48858	ISABELLA	USA	Biomedical Research and Research Training	001	3	4/16/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2021	CENTRAL MICHIGAN UNIVERSITY	119 BOVEE UNIVERSITY CTR	MOUNT PLEASANT	MI	48858	ISABELLA	USA	Biomedical Research and Research Training	000	3	4/16/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $99,998 )
2022	2022	CENTRAL MICHIGAN UNIVERSITY (INC)	119 BOVEE UNIVERSITY CENTER	MOUNT PLEASANT	MI	48858	ISABELLA	USA	Biomedical Research and Research Training	000	3	7/22/2022	SUPPLEMENT FOR EXPANSION	$99,998
														Subtotal = $99,998

Issue Date FY: 2021 ( Subtotal = $424,082 )
2021	2021	CENTRAL MICHIGAN UNIVERSITY (INC)	119 BOVEE UNIVERSITY CENTER	MOUNT PLEASANT	MI	48858	ISABELLA	USA	Biomedical Research and Research Training	000	3	3/4/2021	COMPETING CONTINUATION	$424,082
														Subtotal = $424,082

Issue Date FY: 2018 ( Subtotal = -$222 )
2018	2013	CENTRAL MICHIGAN UNIVERSITY (INC)	119 BOVEE UNIVERSITY CENTER	MOUNT PLEASANT	MI	48858	ISABELLA	USA	Biomedical Research and Research Training	000	2	10/19/2017	COMPETING CONTINUATION	-$222
														Subtotal = -$222

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2013	CENTRAL MICHIGAN UNIVERSITY (INC)	119 BOVEE UNIVERSITY CENTER	MOUNT PLEASANT	MI	48858	ISABELLA	USA	Biomedical Research and Research Training	000	2	11/10/2016	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $313,953 )
2013	2013	CENTRAL MICHIGAN UNIVERSITY, WCMU-TV CHANNEL 14	Herbert H. Grace A. Dow College of	MOUNT PLEASANT	MI	48858	ISABELLA	USA	Biomedical Research and Research Training	000	2	1/14/2013	COMPETING CONTINUATION	$313,953
														Subtotal = $313,953

Issue Date FY: 2009 ( Subtotal = $43,942 )
2009	2009	CENTRAL MICHIGAN UNIVERSITY, WCMU-TV CHANNEL 14	Herbert H. Grace A. Dow College of	MOUNT PLEASANT	MI	48858	ISABELLA	USA	Biomedical Research and Research Training	000	1	1/27/2009	SUPPLEMENT FOR EXPANSION	$20,802
2009	2009	CENTRAL MICHIGAN UNIVERSITY, WCMU-TV CHANNEL 14	Herbert H. Grace A. Dow College of	MOUNT PLEASANT	MI	48858	ISABELLA	USA	Biomedical Research and Research Training	001	1	4/27/2009	SUPPLEMENT FOR EXPANSION	$23,140
														Subtotal = $43,942

Issue Date FY: 2008 ( Subtotal = $204,972 )
2008	2008	CENTRAL MICHIGAN UNIVERSITY, WCMU-TV CHANNEL 14	**	MOUNT PLEASANT	MI	48858	ISABELLA	USA	Biomedical Research and Research Training	000	1	6/26/2008	NEW	$204,972
														Subtotal = $204,972

Grand Total All Awards = $1,084,834

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The role of copines in the regulation of the actin cytoskeleton and membrane trafficking

Award Number: R15GM078089

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: 07/01/2008

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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