2003 — 2007 |
Bergmann, Andreas |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Programmed Cell Death (Apoptosis) in Drosophila @ University of Texas Md Anderson Can Ctr
Apoptosis is a physiological process of cell death that is critical for normal development and tissue homeostasis. Defects in the regulation of apoptotic mechanisms contribute to the pathogenesis of multiple diseases, including those with reduced rates of apoptosis (cancer, autoimmunity) or with excessive cell death (neurodegeneration, stroke, myocardial infarction). The primary focus of this proposal is to elucidate the genetic mechanisms that regulate and execute cell death in the context of a developing organism. We are utilizing the highly accessible genetic model organism Drosophila melanogaster. In Drosophila, the basic components of the cell death machinery are conserved. Homologs of caspases, ced-4/Apaf-1, and lAPs have been identified. We have performed a genetic mutagenesis screen aimed at identifying mutants in components of the cell death machinery in Drosophila. These mutants are extremely informative for the genetic dissection of the Drosophila cell death pathway. For instance, genetic analysis of a subset of these mutants identified the Ras/MAPK pathway as important negative regulator of Hid, one of the cell death-inducing genes in flies. This finding is significant as 30% of human tumors are associated with oncogenic forms of Ras. Therefore, we devote two specific aims to analyze this interaction. We will determine the biochemical basis of Ras/MAPK-induced inhibition of Hid, and we will molecularly identify an additional gene, shes, that appears to control the MAPK/Hid interaction. Caspases, the principal effectors of apoptosis, are under tight genetic control, lAPs inhibit the activity of caspases, whereas Ced-4/Apaf-l-like proteins are required for their activation. How lAPs and Ced-4/Apaf-1- like proteins coordinate caspase activation is poorly understood. Using mutants of the Drosophila homologs of lAPs and Ced-4/Apaf-1 we will dissect the genetic requirement of these genes for the control of caspase activation. Finally, we propose a novel approach that will permit us to isolate additional as yet uncharacterized components of the Drosophila cell death pathway. The information obtained in these experiments will provide new insights into human diseases where deregulation of apoptosis is known to occur and may lead to new strategies for therapeutic intervention.
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0.939 |
2007 — 2010 |
Bergmann, Andreas |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genetic Control of Non-Autonomous Survival in Drosophila @ Univ of Massachusetts Med Sch Worcester
DESCRIPTION (provided by applicant): Cell/cell communication controls many aspects of cellular physiology including cell proliferation, cell differentiation and cell death/survival. However, the complexity of multi-cellular organisms has made it difficult to obtain a comprehensive understanding of all extracellular signaling mechanisms controlling these aspects. This research project focuses on the control of cell survival by extracellular, or non-autonomous, signaling. We have identified mutants in tumor-suppressor-like genes that control the secretion of extra-cellular factors which promote the survival of neighboring cells. These studies reveal interactions between cells which are very relevant for tissue homeostasis, and abnormalities may be directly linked to the parthenogenesis of human diseases including cancer. For example, animals containing mutant clones of these tumor suppressor-like genes are characterized by tissue overgrowth and tumor-like masses. In some of these mutants, Notch activity is inappropriately activated which stimulates proliferation and survival in a non-autonomous manner. Inappropriate Notch activation has been implicated for the genesis of many human cancers. Our data demonstrate that cell proliferation is not sufficient for generation of the tumor masses;instead increased cell survival is necessary for full development of tumors. Therefore, an understanding of the genetic and molecular mechanisms that control non-autonomous cell survival is crucial for the prevention and treatment of these diseases. It is the main goal of this proposal to further our understanding about the mechanisms that regulate non-autonomous survival. For this purpose, we are using the highly accessible genetic model organism Drosophila melanogaster. Our specific aims are: 1. Identify the genes in the signal-sending cell that control non-autonomous cell survival. 2. Identify the mechanisms which lead to secretion of signaling molecules that control cell survival in neighboring cells. 3. Identify the signals and the mechanisms in the signal-receiving cell that control non-autonomous survival. This project will be the first systematic approach to identify all genes and mechanisms that control non- autonomous survival in any organism. The characterization of these genes may have significant implications for the understanding of human diseases, and may help developing drugs and therapies to treat these diseases.
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0.969 |
2007 — 2010 |
Bergmann, Andreas |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Induction of Programmed Cell Death by Cellular Mis-Specification @ Univ of Massachusetts Med Sch Worcester
DESCRIPTION (provided by applicant): The work proposed here is intended to elucidate the mechanisms by which cells that fail to adopt appropriate fate induce programmed cell death. Normal development and homeostasis requires proper specification and cellular differentiation. However, interference with the establishment of cellular fates and cellular functions can lead to the induction of cell death. This strategy might guard the organism against developmental errors, because if these cells were not removed, they might cause malignancies such as cancer. However, under pathological conditions the same strategy may cause the inappropriate death of cells giving rise to congenital defects during development or other conditions such as neurodegenerative disorders. Thus, a detailed investigation of the underlying mechanisms will provide new insights into human diseases in which deregulation of apoptosis is known to occur and may lead to new strategies for therapeutic intervention. It is unknown why a cell dies that receives no or an incorrect developmental signal. In the genetic model organism Drosophila melanogaster, a number of mutants exist that block normal cellular specification and differentiation. Subsequently, these cells undergo cell death. Thus, these mutants provide an excellent genetic model to study the regulation and onset of this form of cell death. We have determined that cellular mis- specification is the underlying cause of cell death in these mutants. The cell death-inducing gene hid is specifically up-regulated in mis-specified cells, suggesting that mis-specification-induced cell death is the result of an active gene-directed process. We postulate that a mechanism monitors the cell's ability to develop correctly. If the cell fails to do so, the monitoring mechanism triggers the transcriptional induction of hid and induces cell death. To genetically and molecularly characterize the postulated monitoring mechanism we will (1) analyze the promoter of the hid gene and identify the factor(s) binding to it in response to mis-specification, (2) analyze the genetic requirement of a number of genes identified in a microarray analysis for mis- specification-induced cell death, and (3) perform genetic screens to identify genes which are required for this process. It is the goal of this proposal to gain a comprehensive understanding of the mechanisms underlying this interesting biological phenomenon, and to exploit this knowledge for therapeutic purposes. This project investigates the mechanisms by which cells die if they do not receive the correct developmental information. These incorrectly informed cells resemble cancer cells, and the observation that they die may protect the organism from several common diseases. Understanding the mechanisms of this process may lead to new therapeutic interventions for cancer, and may also be relevant for treatment of neurodegenerative diseases.
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0.969 |
2009 — 2012 |
Bergmann, Andreas |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genetic Control of Programmed Cell Death in Drosophila @ University of Tx Md Anderson Can Ctr
DESCRIPTION (provided by applicant): Genetic control of Programmed Cell Death in Drosophila Programmed cell death (apoptosis) is a physiological process of cell death that is critical for normal development and tissue homeostasis. Defects in the regulation of cell death mechanisms 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). The overall objective of our research is to gain a comprehensive understanding of the biological principles that underlie the regulation of cell death in the context of a multi-cellular organism, to identify and characterize the genes involved in this process, and to develop methods to manipulate them. Knowledge obtained in these studies will provide new insights into diseases that are associated with altered rates of apoptosis. We are using the genetic model organism Drosophila melanogaster in these studies. During Drosophila development many cells die by apoptosis. As in vertebrates, this cell death is not genetically predetermined in a lineage-restricted manner, but is dependent on environmental circumstances. Thus, Drosophila shares this developmental plasticity with vertebrates. Therefore, molecular genetic studies in Drosophila promise considerable potential for advancing our understanding of the basic control mechanisms involved in the regulation of apoptosis in vertebrates including humans. In the previous funding period we have performed genetic screens aimed at identifying genes involved in the control of programmed cell death. We have identified approximately 30 genes which directly or indirectly regulate cell death. It is the overall goal to characterize these genes phenotypically and molecularly, and to reveal their function for the control of programmed cell death. Finally, we wish to extend our screening efforts to the X chromosome which contains about 20% of the Drosophila genes. The characterization of these genes may have significant implications for the understanding of human diseases, and may help developing drugs and therapies to treat these diseases. PUBLIC HEALTH RELEVANCE: This project investigates the genes and mechanisms that control Programmed Cell Death or Apoptosis. We have identified ~ 30 genes involved in the control of Programmed Cell Death which we wish to characterize. Understanding the mechanisms of this genes will lead to new therapeutic interventions for cancer, and may also be relevant for treatment of neurodegenerative diseases.
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0.969 |
2013 — 2016 |
Bergmann, Andreas |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genetic Control of Programmed Cell Death in Drosphila @ Univ of Massachusetts Med Sch Worcester
DESCRIPTION (provided by applicant): Genetic Control of Programmed Cell Death in Drosophila. Programmed cell death (PCD) or apoptosis is a physiological process that is critical for normal development and tissue homeostasis. Defects in the regulation of PCD 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). The overall objective of our research is to gain a comprehensive understanding of the biological principles that underlie the regulation of PCD in the context of a multi-cellular organism, to identify and characterize the genes involved in this process, and to develop methods to manipulate them. Knowledge obtained in these studies will provide new insights into diseases that are associated with altered rates of apoptosis. We are using the genetic model organism Drosophila melanogaster for these studies. During Drosophila development many cells die by PCD. As in vertebrates, this cell death is not genetically predetermined in a lineage-restricted manner, but is dependent on environmental circumstances. Thus, Drosophila shares this developmental plasticity with vertebrates. Therefore, molecular genetic studies in Drosophila promise considerable potential for advancing our understanding of the basic control mechanisms involved in the regulation of apoptosis in vertebrates including humans. In the previous funding periods, we have performed genetic screens aimed at identifying genes involved in the control of PCD. We have identified approximately 30 genes which directly or indirectly regulate cell death. It is the overall goal to characterize these genes phenotypically and molecularly, and to reveal their function for the control of PCD. We have already revealed new biological principles by which cells control death and survival and will continue to do so in the future. Furthermore, these studies elucidate mechanisms by which potential tumor cells increase their resistance to apoptosis, a hallmark of cancer. Therefore, the characterization of these genes may have significant implications for the understanding of human diseases, and may help developing drugs and therapies to treat these diseases.
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0.969 |
2013 — 2016 |
Bergmann, Andreas |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Apoptosis For Regenerative Proliferation @ Univ of Massachusetts Med Sch Worcester
DESCRIPTION (provided by applicant): Apoptosis-induced proliferation (AiP) describes the recently made discovery that apoptotic cells have the ability to induce proliferation of neighboring surviving cells, thus compensating for their loss. For instance, despite massive apoptotic tissue loss of up to 60% triggered by ionizing radiation, Drosophila wing imaginal discs induce regenerative cell proliferation which generates adult wings of normal proportion and size. 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 a non-apoptotic function. Although progress has been made in the last few years, it is still poorly understood how caspases promote this non- apoptotic role in regenerative proliferation. The overall objective of this project is to identify the genes and elucidate the mechanisms of AiP using Drosophila as a model of gene discovery. Our approach is to induce apoptosis upstream, but simultaneously block apoptosis downstream of its AiP-promoting activity. Under these conditions, cells are kept alive ('undead'), but can still promote AiP because the block of apoptosis is downstream of its AiP-promoting activity. Because 'undead' cells do not die, but continue to promote AiP, they produce significant overgrowth phenotypes which provide convenient assays for genetic screening. These screening assays followed by phenotypic characterization of the identified genes will be explored in this project to address the objective. This project is also very relevant for understanding of human cancer. There are many similarities between tumor cells and 'undead' cells. Tumor cells are often apoptosis-incompetent due to inactivation of apoptotic genes or upregulation of anti-apoptotic genes. If this block of apoptosis occurs downstream of a potentially AiP-inducing activity of 'undead' tumor cells, this activity may significantly contribute to tumor growth which has indeed recently been shown. Furthermore, radio- and chemotherapy attempt to cure cancer by killing tumor cells. However, relapse of treated tumors is frequently observed and may be due to AiP-promoting activity of 'undead' tumor cells. In summary, this project promises to improve our understanding of both regenerative proliferation under normal conditions and tumor phenotypes under pathological conditions.
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0.969 |
2016 — 2020 |
Bergmann, Andreas |
R35Activity Code Description: To provide long term support to an experienced investigator with an outstanding record of research productivity. This support is intended to encourage investigators to embark on long-term projects of unusual potential. |
Genetic Control of Programmed Cell Death (Apoptosis) and Compensatory Proliferation in Drosophila @ Univ of Massachusetts Med Sch Worcester
? DESCRIPTION (provided by applicant): Programmed cell death (PCD) or apoptosis is a physiological process that is critical for normal development and tissue homeostasis. Defects in the regulation of PCD 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). Apoptosis-induced proliferation (AiP) describes the recently made discovery that apoptotic cells have the ability to induce proliferation of neighboring surviving cells, thus compensating for their loss. For instance, despite massive apoptotic tissue loss of up to 60% triggered by ionizing radiation, Drosophila wing imaginal discs induce regenerative cell proliferation which generates adult wings of normal proportion and size. 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 a non-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 the context of 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 genetic model organism Drosophila melanogaster for these studies. During Drosophila development many cells die by apoptosis. This cell death shares this developmental plasticity with vertebrates. Genetic screening for gene discovery and molecular genetic analysis in Drosophila promise considerable potential for advancing our understanding of the basic control mechanisms involved in the regulation of apoptosis and AiP in vertebrates including humans. This program is also 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, recent evidence has suggested that 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. In summary, this program promises to improve our understanding of apoptosis and regenerative proliferation under normal conditions and tumor phenotypes under pathological conditions.
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0.969 |
2021 |
Bergmann, Andreas |
R35Activity Code Description: To provide long term support to an experienced investigator with an outstanding record of research productivity. This support is intended to encourage investigators to embark on long-term projects of unusual potential. |
Mechanisms and Consequences of Programmed Cell Death (Apoptosis) and Compensatory Proliferation in Drosophila @ Univ of Massachusetts Med Sch Worcester
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.
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0.969 |