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Mechanisms and consequences of programmed cell death (apoptosis) and compensatory proliferation in Drosophila

Award Number: R35GM118330
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Mechanisms and Consequences of Apoptosis and Apoptosis-induced Proliferation in Drosophila Principal Investigator: Andreas Bergmann, Ph.D. University of Massachusetts Medical School, Worcester, MA Apoptosis is the major form of cell death that is critical for normal development and tissue homeostasis of multi-cellular organisms. Defects in the regulation of apoptosis contribute to the pathogenesis of multiple diseases including those associated with reduced rates of cell death (cancer, autoimmunity) or with excessive cell death (neurodegeneration, stroke, myocardial infarction). Apoptotic cells interact with and influence the behavior of their cellular environment by releasing anti-inflammatory, pro- and anti-apoptotic as well as mitogenic signals. The release of the latter triggers Apoptosis-induced Proliferation (AiP) which describes the ability of apoptotic cells to induce regenerative proliferation of neighboring surviving cells, thus compensating for their loss. Unexpectedly, evidence obtained in several organisms including Drosophila, Xenopus, Hydra, Mouse and human cancer suggests that regenerative AiP of amputated or otherwise damaged tissues including tumors depends on apoptotic caspases (highly specific cell death proteases) in addition to, but independently of, their apoptotic function. The overall objective of this scientific program is to gain a comprehensive understanding of the biological principles that underlie the regulation of apoptosis and AiP in a multi-cellular organism, to identify and characterize the genes involved in these processes, and to develop methods to manipulate them. We are using the powerful genetic model organism Drosophila melanogaster for these studies. We have developed genetic models of apoptosis and AiP, and initiated forward genetic screens that directly assessed the genetic basis of these fundamental processes. This application focuses on four key questions. 1. How is the fine-tuning of caspase activity achieved? 2. What are the proteolytic targets of caspases for non-apoptotic functions? 3. How do caspases control the generation of reactive oxygen species (ROS) for AiP? 4. How do macrophages (hemocytes) adopt an activated phenotype for growth control? This program is very relevant for understanding of human cancer. Our studies elucidate mechanisms by which potential tumor cells increase their resistance to apoptosis, a hallmark of cancer, which may generate immortalized (undead) cells. Moreover, apoptotic tumor cells promote caspase-dependent AiP. For example, although radio- and chemotherapy attempt to cure cancer by killing tumor cells, relapse of treated tumors is frequently observed which may be due to an AiP-promoting activity of dying tumor cells. Therefore, the results of this research program will significantly improve our understanding of apoptosis and regenerative proliferation under normal conditions, and tumor phenotypes under pathological conditions.


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 = $0 )
2025	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	9	11/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $721,156 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	9	7/24/2024	NON-COMPETING CONTINUATION	$721,156
														Subtotal = $721,156

Issue Date FY: 2023 ( Subtotal = $721,156 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	8	7/11/2023	NON-COMPETING CONTINUATION	$721,156
														Subtotal = $721,156

Issue Date FY: 2022 ( Subtotal = $721,156 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	003	7	7/28/2022	NON-COMPETING CONTINUATION	$721,156
2022	2021	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	002	6	4/3/2022	COMPETING CONTINUATION	$153,591
2022	2020	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	5	4/3/2022	NON-COMPETING CONTINUATION	-$28,591
2022	2020	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	001	5	4/3/2022	SUPPLEMENT FOR EXPANSION	-$125,000
														Subtotal = $721,156

Issue Date FY: 2021 ( Subtotal = $721,156 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	6	7/8/2021	COMPETING CONTINUATION	$721,156
														Subtotal = $721,156

Issue Date FY: 2020 ( Subtotal = $825,152 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	5	7/30/2020	NON-COMPETING CONTINUATION	$700,152
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	001	5	9/15/2020	SUPPLEMENT FOR EXPANSION	$125,000
														Subtotal = $825,152

Issue Date FY: 2019 ( Subtotal = $700,152 )
2019	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	4	7/24/2019	NON-COMPETING CONTINUATION	$700,152
														Subtotal = $700,152

Issue Date FY: 2018 ( Subtotal = $700,152 )
2018	2018	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	3	7/17/2018	NON-COMPETING CONTINUATION	$700,152
														Subtotal = $700,152

Issue Date FY: 2017 ( Subtotal = $700,152 )
2017	2017	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	2	7/17/2017	NON-COMPETING CONTINUATION	$700,152
														Subtotal = $700,152

Issue Date FY: 2016 ( Subtotal = $1 )
2016	2016	UNIVERSITY OF MASSACHUSETTS	406 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Biomedical Research and Research Training	000	1	7/22/2016	NEW	$1
														Subtotal = $1

Grand Total All Awards = $5,810,233

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Mechanisms and consequences of programmed cell death (apoptosis) and compensatory proliferation in Drosophila

Award Number: R35GM118330

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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