ROLES OF DENDRITIC CELLS IN IMMUNE REGULATION
Jin Wang
Baylor College Of Medicine, 1 Baylor Plaza, Houston, Tx 77030-3498
Grant 5R01AI074949-04 from National Institute Of Allergy And Infectious Diseases
Abstract: Understanding the mechanisms for the breakdown of self-tolerance in autoimmunity is essential for the development of strategies to prevent and treat autoimmune diseases. Abundant evidence has shown that defective apoptosis in the immune system is associated with the development of systemic autoimmune diseases in humans and mice. However, inhibition of apoptosis in lymphocytes alone is not sufficient to break immune tolerance, indicating that impaired apoptosis in other cell types plays a critical role in the breakdown of self-tolerance. Targeted inhibition of apoptosis in dendritic cells (DCs) has been shown to induce systemic autoimmune responses. Experiments are proposed to test the hypothesis that apoptosis in DCs is essential for limiting lymphocyte activation and preventing autoimmunity in the following specific aims 1) to characterize the apoptosis pathways in DCs. Death receptor-mediated and mitochondrion-dependent apoptosis pathways will be characterized in DCs. Preliminary studies suggested that the lifespan of DC subsets in vivo was correlating to the molecular ratios between anti-apoptotic and pro-apoptotic bcl-2 family members. Experiments will be performed to further characterize the bcl-2-regulated mitochondrial apoptosis pathways in regulating DC apoptosis; 2) to test the hypothesis that defective apoptosis in DCs contributes to dysregulated lymphocyte activation. The lifespan of DCs can potentially influence immune responses by affecting the duration of DCs in stimulating lymphocytes. The potentials for apoptosis-deficient DCs in over- activating lymphocytes will be examined; and 3) to test the hypothesis that defective apoptosis in DCs contributes to the development of autoimmunity. Studies will be performed to examine whether DCs harboring apoptosis deficiency in the mitochondrial apoptosis pathways leads to the development of autoimmunity. Experiments are proposed to test the hypothesis that apoptosis regulates DC homeostasis and immunogenicity, and defective apoptosis in DCs contributes to the onset of autoimmunity. In the long term, the knowledge gained from these studies will be used to develop more specific and effective strategies to prevent the onset of autoimmunity by targeting apoptosis in DCs
Keywords: APC; Activated Lymphocyte; Affect; Antigen-Presenting Cells; Apaf-3 protein; Apoptosis; Apoptosis Pathway; Apoptotic; Apoptotic Protease Activating Factor 3; Apoptotic Protease MCH-6; Autoimmune Diseases; Autoimmune Responses; Autoimmune Status; Autoimmunity; Autoregulation; Blast Transformation; Blastogenesis; CASP9 Protein; Caspase 9, Apoptosis-Related Cysteine Protease; Caspase Inhibitor; Cell Death, Programmed; Cells; Cessation of life; Death; Dendritic Cells; Development; Family member; Homeostasis; Human; Human, General; ICE-LAP6; ICE-LAP6 protein; ICE-Like Apoptotic Protease 6; Immune; Immune Tolerance; Immune response; Immune system; Immunologic Accessory Cells; Immunologic Tolerance; Inhibition of Apoptosis; Investigators; Knowledge; Length of Life; Longevity; Lymphoblast Transformation; Lymphocyte; Lymphocyte Activation; Lymphocyte Stimulation; Lymphocyte Transformation; Lymphocytic; Mammals, Mice; Man (Taxonomy); Man, Modern; Mch6 protein; Mediating; Mice; Mitochondria; Molecular; Monocytes / Macrophages / APC; Murine; Mus; Physiological Homeostasis; Play; Programs (PT); Programs [Publication Type]; Receptor Protein; Regulation; Regulatory T-Lymphocyte; Research Personnel; Researchers; Role; Self Tolerance; T-Cell Activation; Testing; Transgenic Mice; Veiled Cells; accessory cell; apoptosis in lymphocytes; autoimmune disorder; body system, allergic/immunologic; caspase-9; cell type; experiment; experimental research; experimental study; host response; immune system tolerance; immune unresponsiveness; immunogenicity; immunological paralysis; immunoresponse; in vivo; life span; lifespan; lymph cell; lymphocyte apoptosis; mitochondrial; organ system, allergic/immunologic; prevent; preventing; programs; receptor; research study; self recognition (immune); social role; systemic autoimmune disease
Project start date: 2007-06-01
Project end date: 2012-05-31
Budget start date: 1-JUN-2010
Budget end date: 31-MAY-2011
5R01AI074949-04 (2010): $327777
Sponsored Links Excellgen http://Excellgen.com
ROLES OF DENDRITIC CELLS IN IMMUNE REGULATION
Jin Wang
Baylor College Of Medicine, 1 Baylor Plaza, Houston, Tx 77030-3498
Grant 5R01AI074949-03 from National Institute Of Allergy And Infectious Diseases
Abstract: Understanding the mechanisms for the breakdown of self-tolerance in autoimmunity is essential for the development of strategies to prevent and treat autoimmune diseases. Abundant evidence has shown that defective apoptosis in the immune system is associated with the development of systemic autoimmune diseases in humans and mice. However, inhibition of apoptosis in lymphocytes alone is not sufficient to break immune tolerance, indicating that impaired apoptosis in other cell types plays a critical role in the breakdown of self-tolerance. Targeted inhibition of apoptosis in dendritic cells (DCs) has been shown to induce systemic autoimmune responses. Experiments are proposed to test the hypothesis that apoptosis in DCs is essential for limiting lymphocyte activation and preventing autoimmunity in the following specific aims 1) to characterize the apoptosis pathways in DCs. Death receptor-mediated and mitochondrion-dependent apoptosis pathways will be characterized in DCs. Preliminary studies suggested that the lifespan of DC subsets in vivo was correlating to the molecular ratios between anti-apoptotic and pro-apoptotic bcl-2 family members. Experiments will be performed to further characterize the bcl-2-regulated mitochondrial apoptosis pathways in regulating DC apoptosis; 2) to test the hypothesis that defective apoptosis in DCs contributes to dysregulated lymphocyte activation. The lifespan of DCs can potentially influence immune responses by affecting the duration of DCs in stimulating lymphocytes. The potentials for apoptosis-deficient DCs in over- activating lymphocytes will be examined; and 3) to test the hypothesis that defective apoptosis in DCs contributes to the development of autoimmunity. Studies will be performed to examine whether DCs harboring apoptosis deficiency in the mitochondrial apoptosis pathways leads to the development of autoimmunity. Experiments are proposed to test the hypothesis that apoptosis regulates DC homeostasis and immunogenicity, and defective apoptosis in DCs contributes to the onset of autoimmunity. In the long term, the knowledge gained from these studies will be used to develop more specific and effective strategies to prevent the onset of autoimmunity by targeting apoptosis in DCs
Keywords: APC; Activated Lymphocyte; Affect; Antigen-Presenting Cells; Apaf-3 protein; Apoptosis; Apoptosis Pathway; Apoptotic; Apoptotic Protease Activating Factor 3; Apoptotic Protease MCH-6; Autoimmune Diseases; Autoimmune Responses; Autoimmune Status; Autoimmunity; Autoregulation; Blast Transformation; Blastogenesis; CASP9 Protein; Caspase 9, Apoptosis-Related Cysteine Protease; Caspase Inhibitor; Cell Death, Programmed; Cells; Cessation of life; Death; Dendritic Cells; Development; Family member; Homeostasis; Human; Human, General; ICE-LAP6; ICE-LAP6 protein; ICE-Like Apoptotic Protease 6; Immune; Immune Tolerance; Immune response; Immune system; Immunologic Accessory Cells; Immunologic Tolerance; Inhibition of Apoptosis; Investigators; Knowledge; Length of Life; Longevity; Lymphoblast Transformation; Lymphocyte; Lymphocyte Activation; Lymphocyte Stimulation; Lymphocyte Transformation; Lymphocytic; Mammals, Mice; Man (Taxonomy); Man, Modern; Mch6 protein; Mediating; Mice; Mice, Transgenic; Mitochondria; Molecular; Monocytes / Macrophages / APC; Murine; Mus; Physiological Homeostasis; Play; Programs (PT); Programs [Publication Type]; Receptor Protein; Regulation; Research Personnel; Researchers; Role; Self Tolerance; T-Cell Activation; Testing; Transgenic Mice; Veiled Cells; accessory cell; apoptosis in lymphocytes; autoimmune disorder; body system, allergic/immunologic; caspase-9; cell type; experiment; experimental research; experimental study; host response; immune system tolerance; immune unresponsiveness; immunogenicity; immunological paralysis; immunoresponse; in vivo; life span; lifespan; lymph cell; lymphocyte apoptosis; mitochondrial; organ system, allergic/immunologic; prevent; preventing; programs; receptor; research study; self recognition (immune); social role; systemic autoimmune disease
Project start date: 2007-06-01
Project end date: 2012-05-31
Budget start date: 1-JUN-2009
Budget end date: 31-MAY-2010
5R01AI074949-03 (2009): $331088
5R01AI074949-02 (2008): $331088
Grants awarded to Jin Wang
Roles Of Dendritic Cells In Immune Regulation
Jin Wang
Baylor College Of Medicine 1 Baylor Plaza Houston, Tx 770303498
Grant 1R01AI074949-01 from National Institute Of Allergy And Infectious Diseases IRG: TTT
Abstract: Understanding the mechanisms for the breakdown of self-tolerance in autoimmunity is essential for the development of strategies to prevent and treat autoimmune diseases. Abundant evidence has shown that defective apoptosis in the immune system is associated with the development of systemic autoimmune diseases in humans and mice. However, inhibition of apoptosis in lymphocytes alone is not sufficient to break immune tolerance, indicating that impaired apoptosis in other cell types plays a critical role in the breakdown of self-tolerance. Targeted inhibition of apoptosis in dendritic cells (DCs) has been shown to induce systemic autoimmune responses. Experiments are proposed to test the hypothesis that apoptosis in DCs is essential for limiting lymphocyte activation and preventing autoimmunity in the following specific aims 1) to characterize the apoptosis pathways in DCs. Death receptor-mediated and mitochondrion-dependent apoptosis pathways will be characterized in DCs. Preliminary studies suggested that the lifespan of DC subsets in vivo was correlating to the molecular ratios between anti-apoptotic and pro-apoptotic bcl-2 family members. Experiments will be performed to further characterize the bcl-2-regulated mitochondrial apoptosis pathways in regulating DC apoptosis; 2) to test the hypothesis that defective apoptosis in DCs contributes to dysregulated lymphocyte activation. The lifespan of DCs can potentially influence immune responses by affecting the duration of DCs in stimulating lymphocytes. The potentials for apoptosis-deficient DCs in over- activating lymphocytes will be examined; and 3) to test the hypothesis that defective apoptosis in DCs contributes to the development of autoimmunity. Studies will be performed to examine whether DCs harboring apoptosis deficiency in the mitochondrial apoptosis pathways leads to the development of autoimmunity. Experiments are proposed to test the hypothesis that apoptosis regulates DC homeostasis and immunogenicity, and defective apoptosis in DCs contributes to the onset of autoimmunity. In the long term, the knowledge gained from these studies will be used to develop more specific and effective strategies to prevent the onset of autoimmunity by targeting apoptosis in DCs.
Keywords: apoptosis, dendritic cell, role, antigen, autoimmunity, cell, cell type, cysteine endopeptidase, death, emotion, family, genetically modified animal, homeostasis, human, immune response, immune system, immune tolerance /unresponsiveness, laboratory mouse, lead, leukocyte activation /transformation, lymphocyte, mitochondria, play, receptor, suppression
Project start date: 2007-06-01
Project end date: 2012-05-31
1R01AI074949-01 (2007): $337500
ACTIVATION AND IN VIVO FUNCTIONS OF INITIATOR CASPASES
Jin Wang
Baylor College Of Medicine, 1 Baylor Plaza, Houston, Tx 77030-3498
Grant 5R01GM087710-07 from National Institute Of General Medical Sciences
Abstract: The intrinsic apoptosis pathway involves the disruption of mitochondria and the releases of mitochondrial proteins, leading to the activation of caspase-9 and a downstream caspase cascade. Although cell death can still proceed in the absence of caspase-9, it was delayed in casapse-9-deficient B cells with significant induction of autophagy. Experiments are proposed to test the hypothesis that the interplay between caspase-9 and autophagy plays an important role in regulating programmed cell death. Autophagy may help to protect against cell death by clearing damaged mitochondria 1) To study the mechanisms for the rescue of caspase-9-deficient B cells after partial loss of mitochondrial membrane potential; 2) To determine the mechanisms by which autophagy promotes the survival of B cells; and 3) To investigate the roles of caspase-9 and autophagy in the regulation of development and functions of lymphocytes in vivo. The interplays between caspase signaling and mitochondrial autophagy in regulating programmed cell death will be investigated. The proposed study will help to gain insights into the molecular mechanisms for the regulation of mitochondrial autophagy during cell death. Mitochondrial quality control by autophagy has been suggested to play essential roles in the prevention against aging, cancer and neurodegenerative diseases. The proposed study may facilitate the development of better strategies for treating diseases involving abnormal mitochondrial autophagy. This project seeks to investigate the regulation of programmed cell death by caspases and autophagy
Keywords: APAF1 Protein; Aging; Apaf-1; Apaf-1 protein; Apaf-1L protein; Apaf-3 protein; Apoptosis; Apoptosis Pathway; Apoptotic Protease Activating Factor; Apoptotic Protease Activating Factor 3; Apoptotic Protease MCH-6; Autophagocytosis; Autophagosome; B blood cells; B-Cells; B-Lymphocytes; Bursa-Dependent Lymphocytes; Bursa-Equivalent Lymphocyte; CASP9 Protein; Cancers; Candidate Disease Gene; Candidate Gene; Caspase 9, Apoptosis-Related Cysteine Protease; Cell Communication and Signaling; Cell Death; Cell Death, Programmed; Cell Function; Cell Process; Cell Signaling; Cell Survival; Cell Viability; Cell physiology; Cell-Death Protease; Cells; Cellular Function; Cellular Physiology; Cellular Process; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Development; Disease; Disorder; Erythroid Cells; Ferricytochrome c; Ferrocytochrome c; ICE-LAP6; ICE-LAP6 protein; ICE-Like Apoptotic Protease 6; ICE-like protease; Intracellular Communication and Signaling; Knock-out; Knockout; Libraries; Lymphocyte Function; Malignant Neoplasms; Malignant Tumor; Mammals, Mice; Mch6 protein; Membrane Potentials; Mice; Mitochondria; Mitochondrial Proteins; Molecular; Murine; Mus; Neurodegenerative Diseases; Neurodegenerative Disorders; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; Organelles; Play; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Prevention; Proliferating; Quality Control; Quelling; RNA Interference; RNA Silencing; RNA Silencings; RNAi; Regulation; Reporting; Resting Potentials; Role; Screening procedure; Senescence; Sequence-Specific Posttranscriptional Gene Silencing; Signal Transduction; Signal Transduction Systems; Signaling; Staging; Stimulus; Subcellular Process; Testing; Transmembrane Potentials; Yeasts; apoptotic protease-activating factor 1; autophagy; biological signal transduction; caspase; caspase-9; cystein protease; cystein proteinase; cysteine endopeptidase; cytochrome c; disease/disorder; experiment; experimental research; experimental study; in vivo; inhibition of autophagy; insight; malignancy; mitochondrial; mitochondrial autophagy; mitochondrial membrane; necrocytosis; neoplasm/cancer; neurodegenerative illness; novel; research study; screening; screenings; senescent; social role
Relevance: Narrative This project seeks to investigate the regulation of programmed cell death by caspases and autophagy
Project start date: 2003-07-01
Project end date: 2013-03-31
Budget start date: 1-APR-2010
Budget end date: 31-MAR-2011
PFA/PA: PA-07-070
5R01GM087710-07 (2010): $341921
1R01AI056210-01 (2003): $169313
SELECTIVE MITOCHONDRIAL AUTOPHAGY IN THE MAINTENANCE OF GENOME STABILITY
Jin Wang
Baylor College Of Medicine, 1 Baylor Plaza, Houston, Tx 77030-3498
Grant 1R21CA152076-01 from National Cancer Institute
Abstract: Autophagy has emerged as a novel mechanism for tumor suppression. It has been postulated that defective autophagy leads to the accumulation of damaged proteins or organelles, resulting in genome instability and cancer. We have observed that a Bcl-2 family member, Nix, is required for selective autophagy of mitochondria that have lost mitochondrial membrane potential. Dysfunctional mitochondria can produce reactive oxygen species to cause DNA damage. However, it is unclear whether selective mitochondrial autophagy is important for preventing damages to mitochondrial and nuclear DNA. We hypothesize that selective mitochondrial autophagy plays a critical role in mitochondrial quality control. Accumulation of dysfunctional mitochondria due to defective autophagy may cause increases in DNA damage, leading to genome instability. We propose 1) to determine the role for mitochondrial autophagy in protecting genome stability; 2) to characterize the molecular mechanisms of specific recognition of dysfunctional mitochondria by autophagosomes. This study may help to reveal molecular events of autophagy as novel biomarkers for mitochondrial quality control in the protection against genome instability and cancer. Narrative This study seeks to identify the molecular events in autophagy as novel biomarkers in mitochondrial quality control and the prevention of genome instability
Keywords: Active Oxygen; Autophagocytosis; Autophagosome; Body Tissues; Cancers; Candidate Disease Gene; Candidate Gene; Cells; DNA; DNA Alteration; DNA Damage; DNA Damage Repair; DNA Injury; DNA Repair; DNA Repair Enzymes; DNA mutation; DNA, Mitochondrial; Deoxyribonucleic Acid; Event; Family member; Fe element; Gene Alteration; Gene Mutation; Genes; Genetic mutation; Genome Instability; Genome Stability; Genomic Instability; Impairment; Iron; Lead; Libraries; Maintenance; Maintenances; Malignant Neoplasms; Malignant Tumor; Mammals, Mice; Membrane Potentials; Mice; Mitochondria; Mitochondrial DNA; Modality; Molecular; Murine; Mus; Nuclear; Nucleotides; Oncogenesis; Organelles; Oxygen Radicals; Pb element; Play; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Prevention; Pro-Oxidants; Production; Proteins; Proteomics; Quality Control; Quelling; RNA Interference; RNA Silencing; RNA Silencings; RNAi; Reactive Oxygen Species; Resting Potentials; Role; S element; Screening procedure; Sequence Alteration; Sequence-Specific Posttranscriptional Gene Silencing; Stability, Genomic; Sulfur; Testing; Tissues; Transmembrane Potentials; Tumor Suppression; Tumor Suppression, Molecular; Unscheduled DNA Synthesis; autophagy; biomarker; erythroid differentiation; gene product; heavy metal Pb; heavy metal lead; insight; malignancy; mitochondrial; mitochondrial autophagy; mitochondrial dysfunction; mitochondrial membrane; mtDNA; neoplasm/cancer; novel; prevent; preventing; public health relevance; screening; screenings; social role; therapeutic development; tumorigenesis
Relevance: Narrative This study seeks to identify the molecular events in autophagy as novel biomarkers in mitochondrial quality control and the prevention of genome instability
Project start date: 2010-07-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: PA-08-144
1R21CA152076-01 (2010): $170194
Roles Of Dendritic Cell Apoptosis In Immune Tolerance
Jin Wang
Immunologybaylor College Of Medicine
1 Baylor Plaza
houston, Tx 770303498
Grant 1K22AI001797-01A1 from National Institute Of Allergy And Infectious Diseases IRG: AITC
Abstract: Adapted from Applicant´s ) Studies are proposed to analyze the apoptosis signaling pathways in dendritic cells and the effects of defective dendritic cell apoptosis on self tolerance. To study dendritic cell apoptosis and immune tolerance, experiments are proposed to 1. To characterize the death pathways in dendritic cells 1a. define the roles of death receptors in dendritic cell apoptosis. lb. Study the signaling molecules in dendritic cell death pathways. 2. To study how maturation of dendritic cells regulates apoptosis. 3. To determine the contribution of defective dendritic cell apoptosis to autoimmunity 3a. Study dendritic cell deletion in an adoptive transfer model using dendritic cells transduced with apoptotic inhibitors. 3b. Study autoimmune responses in transgenic mice expressing apoptotic inhibitors in dendritic cells. Dendritic cells have emerged as a cell type critical for initiating and regulating immune responses. The proposed study may provide insights into the roles of dendritic cell apoptosis in self tolerance and autoimmunity
Keywords: apoptosis, dendritic cell, immune tolerance /unresponsiveness autoimmunity, biological signal transduction, cell differentiation, receptor laboratory mouse, transgenic animal
Project start date: 2001-09-01
Project end date: 2003-08-31
1K22AI001797-01A1 (2001): $160858
Activation And In Vivo Functions Of Initiator Caspases
Jin Wang
Immunologybaylor College Of Medicine
1 Baylor Plaza
houston, Tx 770303498
Grant 5R01AI056210-05 from National Institute Of Allergy And Infectious Diseases IRG: ALY
Keywords: cysteine endopeptidase T lymphocyte, apoptosis, cell, cell proliferation, cytokine, death, dimer, immune system, lead, mitochondria, model, neoplasm /cancer, perinatal, play, receptor, role
Project start date: 2003-07-01
Project end date: 2008-12-31
5R01AI056210-05 (2007): $321078
5R01AI056210-04 (2006): $330668
5R01AI056210-03 (2005): $338625
5R01AI056210-02 (2004): $338625
Sponsored Links Excellgen http://Excellgen.com