Martin John Hessner
Medical College Of Wisconsin
Project start date: 2009-01-01
Project end date: 2013-12-31
Sponsored Links Excellgen http://Excellgen.com
DISSECTION OF CELLULAR INTERACTIONS IN T1DM WITH INTEGRATED FUNCTIONAL GENOMICS
Martin John Hessner, Associate Professor
Medical College Of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, Wi 53226-0509
Grant 5R01AI078713-06 from National Institute Of Allergy And Infectious Diseases
Abstract: Recognizing the power of a systems approach to complex disease, during the initial funding period we developed a highly-controlled three color array and analysis platform focused on acquisition of quality data. Our goal is apply these tools to the events leading to autoimmunity using a unique derivative of the BioBreeding (BB) rat model of type 1 diabetes mellitus (T1DM). BB DRlyp/lyp rats are spontaneously diabetic due to a mutation in the Gimap5 gene, rendering them deficient in regulatory T (TREG) cells. DR+/+ rats possess an intact Gimap5 gene and do not develop spontaneous T1DM, but become diabetic upon depletion of TREG cells. T1DM in BB rats also involves a cytotoxic T cells, since their depletion is protective. Our gene expression studies of prediabetic pancreatic lymph nodes (PLN) have shown that mast cells are terminally activated in DRlyp/lyp animals versus negatively regulated in DR+/+ animals; we have confirmed their functional role through preventing T1DM in rats with two different mast cell inhibiting drugs. Thus, we hypothesize that in addition to cytotoxic T effector cells, mast cells play a crucial early role in DRlyp/lyp diabetogenesis and in spite of their disease predisposition, TREG cells are sufficient to prevent T1DM in DR+/+ rats. We further hypothesize that associated with these states are distinct cytokine milieus, since we find incubation of sera derived from human individuals at risk for T1DM or recent onset T1DM with healthy peripheral blood mononuclear cells (PBMC) induce a characteristic gene expression signature that is distinct from normal controls and long standing T1DM. Importantly, we find observe this molecular signature as much as 5 years prior to T1DM onset. The predictable disease course of the BB rat enables longitudinal dissection of the activities of immune cell subpopulations and examining how these activities are manifested in the periphery. Thus we propose to 1) temporally and spatially dissect the activities of antigen presenting, regulatory, and effector cells at defined pre-onset timepoints through gene expression profiling and histological approaches. 2) The sera of WF, DR+/+ and DRlyp/lyp rats will be longitudinally evaluated for factors that induce gene expression in healthy PBMCs. Presence of candidate mediators and disease time point-specific biomarkers will be confirmed. Understanding the relationship between mast cells, T effector, and TREG cells in autoimmunity and has the potential to establish a new paradigm for immune regulation and create new insights to human disease. Many inflammatory diseases, including type 1 diabetes mellitus (T1DM) become evident only after tissue and organ damage have already progressed. The objective of this proposal is to 1) better understand how and when different immune cell types enter into the immunological cascade that results in T1DM; and 2) how these events manifest themselves in the periphery as biomarkers of disease
Keywords: ATGN; Acidophilic Leukocyte; Animals; Antigens; Assay; Autoimmune Diseases; Autoimmune Status; Autoimmunity; Basophilic Histiocyte; Basophils, Tissue; Bioassay; Biologic Assays; Biological Assay; Blood Eosinophil; Blood Serum; Body Tissues; CCL11 protein; CTL; Cell Communication; Cell Interaction; Cell-Mediated Lympholytic Cells; Cell-to-Cell Interaction; Cells; Characteristics; Color; Common Rat Strains; Complex; Cytolytic T-Cell; Cytotoxic T Cell; Cytotoxic T-Lymphocytes; DISSEC; Data Quality; Development; Diabetes Mellitus, Brittle; Diabetes Mellitus, Insulin-Dependent; Diabetes Mellitus, Juvenile-Onset; Diabetes Mellitus, Ketosis-Prone; Diabetes Mellitus, Sudden-Onset; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type I; Disease; Disorder; Dissection; Drugs; Effector Cell; Environmental Factor; Environmental Risk Factor; Eosinophil Chemotactic Protein; Eosinophilic Granulocyte; Eosinophilic Leukocyte; Eotaxin; Event; Evolution; Exhibits; Expression Profiling; Expression Signature; Funding; Gastrointestinal Tract, Pancreas; Gene Expression; Gene Expression Monitoring; Gene Expression Pattern Analysis; Gene Expression Profile; Gene Expression Profiling; Gene Transcription; Genes; Genetic Alteration; Genetic Change; Genetic Transcription; Genetic defect; Goals; Human; Human, General; Humulin R; IDD; IDDM; IL-1; IL1; IL1 Receptors; Immune; Immune Precipitation; Immune response; Immunity, Innate; Immunity, Native; Immunity, Natural; Immunity, Non-Specific; Immunoprecipitation; In Vitro; Inbred WF Rats; Individual; Inflammatory; Infrastructure; Insulin; Insulin (ox), 8A-L-threonine-10A-L-isoleucine-30B-L-threonine-; Insulin, Regular; Insulin-Dependent Diabetes Mellitus; Interleukin I; Interleukin-1; Interleukin-1 Receptors; Interleukins; Lymph node proper; Lymphocyte-Stimulating Hormone; Macrophage Cell Factor; Mammals, Rats; Man (Taxonomy); Man, Modern; Marrow Eosinophil; Marrow Mast Cell; Measurable; Measurement; Measures; Mediating; Mediator; Mediator of Activation; Mediator of activation protein; Medication; Modeling; Molecular Fingerprinting; Molecular Profiling; Mutation; Natural Immunity; Novolin R; Onset of illness; Organ; PBMC; Pancreas; Pancreatic; Participant; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutic Preparations; Pharmaceutical Preparations; Play; Population; Predisposition; Prevention; Profilings, Gene Expression; Quality, Data; RNA Expression; Rat; Rats, Inbred WF; Rats, Inbred Wistar Furth; Rats, WF; Rats, Wistar Furth; Rattus; Receptors, IL-1; Receptors, Interleukin-1; Regulation; Research Infrastructure; Reticuloendothelial System, Lymph Node; Risk; Role; Sampling; Serum; Small Inducible Cytokine A11; Societies; Stress; Susceptibility; System; System, LOINC Axis 4; Systems Biology; T Helper Factor; T-Cells; T-Lymphocyte; T-Lymphocytes, Cytotoxic; T1 diabetes; T1D; T1DM; Thymus-Dependent Lymphocytes; Time; Tissues; Transcript Expression Analyses; Transcript Expression Analysis; Transcription; Transcription, Genetic; Type 1 diabetes; Weaning; autoimmune disorder; biomarker; cell type; congenic; cost; cytokine; cytotoxic; diabetic; disease onset; disease/disorder; disorder onset; drug/agent; environmental risk; eosinocyte; eosinophil; eotaxin-1; functional genomics; gene expression signature; genome mutation; host response; human disease; immunogen; immunoresponse; in vivo; inhibitor; inhibitor/antagonist; insight; insulin dependent diabetes; islet; juvenile diabetes; juvenile diabetes mellitus; ketosis prone diabetes; lymph gland; lymph nodes; lymphocyte activating factor; mast cell; mastocyte; molecuar profile; molecular signature; non-diabetic; nondiabetic; novel; pathway; prevent; preventing; public health relevance; response; self recognition (immune); social role; thymus derived lymphocyte; tool; transcriptome; type I diabetes; unspecified interleukin
Relevance: Many inflammatory diseases, including type 1 diabetes mellitus (T1DM) become evident only after tissue and organ damage have already progressed. The objective of this proposal is to 1) better understand how and when different immune cell types enter into the immunological cascade that results in T1DM; and 2) how these events manifest themselves in the periphery as biomarkers of disease
Project start date: 2009-01-01
Project end date: 2013-12-31
Budget start date: 1-JAN-2010
Budget end date: 31-DEC-2010
PFA/PA: PA-07-070
5R01AI078713-06 (2010): $345756