Thursday, November 21, 2024 11/21/2024

Spatiotemporal regulation of collective cell behaviors in Drosophila

Award Number: R01GM046425
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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View Award Abstract

Normal tissue development and tumor metastasis require extensive cell movements, and border cell migration in the Drosophila ovary provides a powerful in vivo model. Border cells migrate as a group of two different cell types, a pair of non-migratory polar cells in the center that recruit 6-8 epithelial cells to surround and carry them between nurse cells to the developing oocyte, in a structure called an egg chamber. Using this system, we first discovered the in vivo role of the 21kD GTPase Rac in protrusion and migration, then showed that photoactivation of Rac in one cell could steer the entire cluster. For more than two decades though, we were puzzled that expression of constitutively active Rac in border cells seemed to destroy the entire egg chamber. During the current funding period, we solved this longstanding mystery. We discovered that border cells expressing active Rac kill the nurse cells. Anterior follicle cells normally engulf and kill nurse cells late in oogenesis, and we propose that active Rac prematurely activates this program. A similar mechanism may explain otherwise mysterious immune deficiencies in human patients. Here we propose to continue our exciting investigation of the spatiotemporal control of Rac-mediated cell migration and engulfment in Drosophila. In Aim 1 we propose to elucidate the mechanisms of Rac-mediated cell killing. Taking advantage of the border cell model, we will test the functional effects of each of the known activating Rac mutations that cause immunodeficiencies in patients. We will test the hypothesis that border cells expressing active Rac prematurely activate the normal developmental killing program, and we will define more precisely the role of Rac within the molecular pathway. We will investigate how just six cells can destroy an entire egg chamber, and we will identify the chemical, physical, and adhesive properties that govern target cell selection. In Aim 2, we propose to follow up on our discovery that a basally localized Rac activator is required for border cell cluster cohesion and migration. We will elucidate its relationship to basolateral complex proteins and test whether its primary function is to localize Rac activity to basal surfaces. We will test the hypothesis that basal Rac activity is required to generate basal protrusions that in turn coordinate collective cell behavior. In Aim 3, we will follow up on a screen in which we have identified Rho family activators and inhibitors required in border cells. We propose that border cells require elaborate spatiotemporal control of Rac due to their needs to: maintain apicobasal polarity despite being detached from basement membrane, extend and retract forward-directed protrusions, maintain cohesion under strain, and inhibit inappropriate protrusion. Our ultimate goal is the decipher the Rac regulatory network.


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 = $564,715 )
2024	2024	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	002	32	7/15/2024	NON-COMPETING CONTINUATION	$48,047
2024	2024	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	32	1/16/2024	NON-COMPETING CONTINUATION	$432,446
2024	2024	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	001	32	1/17/2024	SUPPLEMENT FOR EXPANSION	$84,222
														Subtotal = $564,715

Issue Date FY: 2023 ( Subtotal = $549,033 )
2023	2023	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	31	1/12/2023	NON-COMPETING CONTINUATION	$432,447
2023	2023	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	002	31	5/25/2023	SUPPLEMENT FOR EXPANSION	$19,408
2023	2023	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	003	31	6/30/2023	SUPPLEMENT FOR EXPANSION	$49,128
2023	2023	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	001	31	2/14/2023	NON-COMPETING CONTINUATION	$48,050
														Subtotal = $549,033

Issue Date FY: 2022 ( Subtotal = $580,495 )
2022	2022	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	30	2/28/2022	COMPETING CONTINUATION	$580,495
2022	2021	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	001	29	7/26/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $580,495

Issue Date FY: 2021 ( Subtotal = $449,279 )
2021	2021	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	001	29	2/22/2021	NON-COMPETING CONTINUATION	$44,927
2021	2021	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	29	11/24/2020	NON-COMPETING CONTINUATION	$404,352
														Subtotal = $449,279

Issue Date FY: 2020 ( Subtotal = $449,279 )
2020	2020	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	001	28	2/27/2020	NON-COMPETING CONTINUATION	$44,927
2020	2020	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	28	11/28/2019	NON-COMPETING CONTINUATION	$404,352
														Subtotal = $449,279

Issue Date FY: 2019 ( Subtotal = $449,279 )
2019	2019	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	27	11/14/2018	NON-COMPETING CONTINUATION	$449,279
														Subtotal = $449,279

Issue Date FY: 2018 ( Subtotal = $449,335 )
2018	2018	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	003	26	6/19/2018	COMPETING CONTINUATION	$116
2018	2018	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	001	26	12/14/2017	COMPETING CONTINUATION	$449,335
2018	2016	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	002	25	6/19/2018	EXTENSION WITH OR WITHOUT FUNDS	-$116
2018	2016	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	25	12/11/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $449,335

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	25	10/27/2016	EXTENSION WITH OR WITHOUT FUNDS	$24,498
2017	2015	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	24	10/27/2016	NON-COMPETING CONTINUATION	-$24,498
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $499,864 )
2016	2016	UNIVERSITY OF CALIFORNIA-SANTA BARBARA	EXTRAMURAL FNDS/CONTRACTS/GNTS	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	25	6/15/2016	EXTENSION WITH OR WITHOUT FUNDS	$499,864
														Subtotal = $499,864

Issue Date FY: 2015 ( Subtotal = $499,864 )
2015	2015	UNIVERSITY OF CALIFORNIA-SANTA BARBARA	EXTRAMURAL FNDS/CONTRACTS/GNTS	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	24	6/25/2015	NON-COMPETING CONTINUATION	$499,864
														Subtotal = $499,864

Issue Date FY: 2014 ( Subtotal = $499,864 )
2014	2014	UNIVERSITY OF CALIFORNIA-SANTA BARBARA	EXTRAMURAL FNDS/CONTRACTS/GNTS	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	000	23	7/31/2014	NON-COMPETING CONTINUATION	$499,864
														Subtotal = $499,864

Issue Date FY: 2013 ( Subtotal = $498,277 )
2013	2013	UNIVERSITY OF CALIFORNIA-SANTA BARBARA	EXTRAMURAL FNDS/CONTRACTS/GNTS	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Biomedical Research and Research Training	001	22	6/27/2013	COMPETING CONTINUATION	$498,277
2013	2012	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	21	6/24/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $498,277

Issue Date FY: 2012 ( Subtotal = $503,096 )
2012	2012	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	21	12/19/2011	NON-COMPETING CONTINUATION	$458,509
2012	2012	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	21	3/9/2012	NON-COMPETING CONTINUATION	$44,587
														Subtotal = $503,096

Issue Date FY: 2011 ( Subtotal = $503,096 )
2011	2011	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	20	6/29/2011	NON-COMPETING CONTINUATION	$32,014
2011	2011	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	20	12/20/2010	NON-COMPETING CONTINUATION	$471,082
														Subtotal = $503,096

Issue Date FY: 2010 ( Subtotal = $511,436 )
2010	2010	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	19	4/7/2010	NON-COMPETING CONTINUATION	$511,436
														Subtotal = $511,436

Issue Date FY: 2009 ( Subtotal = $746,779 )
2009	2009	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Trans-NIH Recovery Act Research Support	002	18	9/21/2009	SUPPLEMENT FOR EXPANSION	$218,986
2009	2009	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	18	2/20/2009	COMPETING CONTINUATION	$527,793
2009	2007	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	17	2/20/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $746,779

Issue Date FY: 2007 ( Subtotal = $516,580 ) (Continued on the next page)
Grand Total All Awards = $11,712,213

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Spatiotemporal regulation of collective cell behaviors in Drosophila

Award Number: R01GM046425

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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