Andreas Bergmann
Univ Of Massachusetts Med Sch Worcester
Project start date: 2007-09-24
Project end date: 2012-08-31
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Andreas Bergmann
INDUCTION OF PROGRAMMED CELL DEATH BY CELLULAR MIS-SPECIFICATION
Andreas Bergmann, Associate Professor
University Of Texas Md Anderson Can Ctr, Unit 0176, Houston, Tx 77030-4009
Grant 5R01GM074977-03 from National Institute Of General Medical Sciences
Abstract: 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
Keywords: 21+ years old; AIDS; Abdomen; Abdominal; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Address; Adopted; Adult; Animal Model; Animal Models and Related Studies; Animals; Apoplexy; Apoptosis; Apoptosis Pathway; Autoimmune Status; Autoimmunity; Autoregulation; Binding; Binding (Molecular Function); Biologic Phenomena; Biological Phenomena; Birth Defects; Body Tissues; Cancers; Cell Communication and Signaling; Cell Death; Cell Death Induction; Cell Death, Programmed; Cell Function; Cell Process; Cell Signaling; Cell physiology; Cell-Death Protease; Cells; Cellular Function; Cellular Physiology; Cellular Process; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular accident; Cessation of life; Chest; Congenital Abnormality; Congenital Anatomic Abnormality; Congenital Anatomical Abnormality; Congenital Defects; Congenital Deformity; Congenital Malformation; DISSEC; Death; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Deregulation of Apoptosis; Deregulation of Programmed Cell Death; Development; Disease; Disorder; Dissection; Drosophila; Drosophila genus; Drosophila melanogaster; Embryo; Embryonic; Embryonic Tissue; Employee Strikes; Expression Profiling; Expression Signature; Female; Fruit Fly, Drosophila; Frustration; Genes; Genetic Alteration; Genetic Change; Genetic Models; Genetic Screening; Genetic analyses; Genetic defect; Genomics; Goals; Head; Heart failure; Homeostasis; Human, Adult; ICE-like protease; Immunologic Deficiency Syndrome, Acquired; Intracellular Communication and Signaling; Investigation; Knowledge; Lead; Link; Maintenance; Maintenances; Malignant; Malignant - descriptor; Malignant Cell; Malignant Neoplasms; Malignant Tumor; Microarray Analysis; Microarray-Based Analysis; Models, Genetic; Molecular; Molecular Fingerprinting; Molecular Genetic Abnormality; Molecular Interaction; Molecular Profiling; Monitor; Mutation; Nerve Degeneration; Neurodegenerative Diseases; Neurodegenerative Disorders; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; Neuron Degeneration; Organism; Pathogenesis; Pb element; Phenotype; Physiologic; Physiological; Physiological Homeostasis; Play; Position; Positioning Attribute; Prevention; Process; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); Regulation; Regulatory Element; RegulatoryElement; Role; Signal Transduction; Signal Transduction Systems; Signaling; Specific qualifier value; Specified; Strikes; Strikes, Employee; Stroke; Subcellular Process; Testing; Therapeutic; Therapeutic Intervention; Thorace; Thoracic; Thorax; Tissues; Trans-Acting Factors; Trans-Activators; Transactivators; Vascular Accident, Brain; Work; adult human (21+); apoptosis deregulation; biological signal transduction; brain attack; cancer cell; cardiac failure; caspase; cell suicide; cellular suicide; cerebral vascular accident; cystein protease; cystein proteinase; cysteine endopeptidase; disease/disorder; embryo tissue; fruit fly; genetic analysis; genome mutation; heavy metal Pb; heavy metal lead; human disease; insight; interest; intervention therapy; living system; malformation; malignancy; microarray technology; model organism; molecuar profile; molecular signature; mutant; necrocytosis; neoplasm/cancer; neural degeneration; neurodegeneration; neurodegenerative illness; neuronal degeneration; novel therapeutic intervention; response; self recognition (immune); social role; stroke; trans acting factor (genetic); tumor
Project start date: 2007-09-24
Project end date: 2011-08-31
Budget start date: 1-SEP-2009
Budget end date: 31-AUG-2010
PFA/PA: PA-07-070
5R01GM074977-03 (2009): $284900
5R01GM074977-02 (2008): $284900
1R01GM074977-01A1 (2007): $284900
Genetic Control Of Programmed Cell Death In Drosophila
Andreas Bergmann
Biochemistry And Molecular Biologyuniversity Of Texas Md Anderson Can Ctr
Grant 2R01GM068016-06 from National Institute Of General Medical Sciences IRG: DEV1
Abstract: 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. 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
Project start date: 2003-09-19
Project end date: 2012-12-31
GENETIC CONTROL OF NON-AUTONOMOUS SURVIVAL IN DROSOPHILA
Andreas Bergmann, Associate Professor
University Of Texas Md Anderson Can Ctr, Unit 0176, Houston, Tx 77030-4009
Grant 5R01GM081543-03 from National Institute Of General Medical Sciences
Abstract: 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
Keywords: 21+ years old; Adult; Affect; Amino Acids; Animal Model; Animal Models and Related Studies; Animals; Apaf-3 protein; Apoptosis; Apoptosis Pathway; Apoptotic; Apoptotic Protease Activating Factor 3; Apoptotic Protease MCH-6; Autoregulation; BIR Domain; BIR Motif; Baculovirus Inhibitor of Apoptosis Protein Repeat; Binding; Binding (Molecular Function); Body Tissues; CASP9 Protein; Cancers; Caspase 9, Apoptosis-Related Cysteine Protease; Cell Communication; Cell Communication and Signaling; Cell Death; Cell Death, Programmed; Cell Differentiation; Cell Differentiation process; Cell Function; Cell Growth in Number; Cell Interaction; Cell Multiplication; Cell Process; Cell Proliferation; Cell Signaling; Cell Survival; Cell Viability; Cell physiology; Cell-Death Protease; Cell-to-Cell Interaction; Cells; Cellular Function; Cellular Physiology; Cellular Process; Cellular Proliferation; Chromosome 2; Chromosomes, Human, Pair 2; Classification; DIAP1 protein, Drosophila; Data; Development; Disease; Disorder; Drosophila; Drosophila genus; Drosophila inhibitor of apoptosis 1; Drosophila melanogaster; Drug Therapy; Embryo Development; Embryogenesis; Embryonic Development; Endogenous Nitrate Vasodilator; Endothelium-Derived Relaxing Factor; Figs; Figs - dietary; Fruit Fly, Drosophila; GeneHomolog; Generations; Genes; Genetic; Genetic Models; Goals; Homeostasis; Homolog; Homologous Gene; Homologue; Human; Human, Adult; Human, General; IAP Family Protein; IAP Repeat; IAP protein; IAP protein (apoptosis); IAP1, Drosophila; ICE-LAP6; ICE-LAP6 protein; ICE-Like Apoptotic Protease 6; ICE-like protease; Inhibitor of Apoptosis Domain; Intracellular Communication and Signaling; Lead; Link; Maintenance; Maintenances; Malignant Neoplasms; Malignant Tumor; Mammalia; Mammals; Mammals, General; Man (Taxonomy); Man, Modern; Mch6 protein; Methods; Models, Genetic; Molecular Genetic; Molecular Genetics; Molecular Interaction; Mononitrogen Monoxide; N-terminal; NH2-terminal; Nitric Oxide; Nitric Oxide, Endothelium-Derived; Nitrogen Monoxide; Nitrogen Protoxide; Nitrogen oxide; Organism; Parthenogenesis; Pathogenesis; Pathway interactions; Pb element; Pharmacotherapy; Physiological Homeostasis; Prevention; Production; Protein Binding; Proteins; R01 Mechanism; R01 Program; RPG; Research Grants; Research Project Grants; Research Projects; Research Projects, R-Series; Resistance; Role; Screening procedure; Signal Transduction; Signal Transduction Systems; Signaling; Signaling Molecule; Subcellular Process; Systematics; Tissues; Tumor Suppressor Proteins; adult human (21+); aminoacid; biological signal transduction; caspase; caspase-9; cystein protease; cystein proteinase; cysteine endopeptidase; disease/disorder; endothelial cell derived relaxing factor; extracellular; fruit fly; gene product; heavy metal Pb; heavy metal lead; human disease; inhibitor of apoptosis 1, Drosophila; inhibitor-of-apoptosis protein; living system; malignancy; model organism; mutant; necrocytosis; neoplasm/cancer; notch; notch protein; notch receptors; novel; pathway; resistant; screening; screenings; social role; tumor; tumor suppressor
Project start date: 2007-09-01
Project end date: 2011-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2010
5R01GM081543-03 (2009): $292600
5R01GM081543-02 (2008): $292600
1R01GM081543-01 (2007): $292600
Programmed Cell Death (Apoptosis) In Drosophila
Andreas Bergmann
Biochemistry And Molecular Biologyuniversity Of Texas Md Anderson Can Ctr
cancer Center
houston, Tx 770304009
Grant 5R01GM068016-05 from National Institute Of General Medical Sciences IRG: CDF
Abstract: 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
Keywords: Drosophilidae, apoptosis, developmental genetics, genetic regulation, mitogen activated protein kinase, oncogene cysteine endopeptidase, enzyme activity, enzyme inhibitor, enzyme mechanism, genetic screening, homeostasis biological model
Project start date: 2003-09-19
Project end date: 2008-08-31
5R01GM068016-05 (2007): $264875
5R01GM068016-04 (2006): $272786
3R01GM068016-02S1 (2005): $4250
Sponsored Links Excellgen http://Excellgen.com
5R01GM068016-03 (2005): $279350
5R01GM068016-02 (2004): $279350
1R01GM068016-01A1 (2003): $279350
Andreas Bergmann
Univ Of Massachusetts Med Sch Worcester
Project start date: 2003-09-19
Project end date: 2012-12-31