The goal of this Phase I project is the identification of a molecular signature in the T-cell receptor repertoire of early-stage Type 1 Diabetes (T1D) patients that distinguishes these patients from controls. At present, immunomodulatory therapies have not proven useful for treatment of T1D, largely because of adverse side effects and also because pancreatic function has already been compromised by the time symptoms present. A diagnostic product that could detect the very earliest events in breaking tolerance, such as the development of a signature pattern in the repertoire of T-cell receptor (TCR) sequences, would allow for early intervention in high-risk individuals, potentially providing an opportunity for preservation of islet cell function and natural insulin production. Herein, we propose to commercialize our high-throughput TCR( sequencing assay to identify signals in the TCR( sequence repertoire that are indicative of loss of islet cell function. The ability to simultaneously sequence millions of individual T-cell receptor genes in single individuals provides, for the first time, the potential to directly observe disease-associated changes in the immune repertoire, the very set of receptors that evolves as T1D moves from initiation to progressive beta cell destruction. The utility of this signature as a diagnostic tool could expand treatment options for T1D by identifying individuals in the very earliest stages of disease, when therapy and treatment could be most effective.
Public Health Relevance: Type 1 Diabetes (T1D) is usually diagnosed when symptoms present, a stage of disease in which autoimmunity has caused the loss of islet cell function. We propose to identify a signature pattern in the repertoire of T-cell receptor (TCR) sequences that could serve as a diagnostic product to detect the very earliest stage of disease. A diagnosis at earlier stages would allow for early intervention in high-risk individuals, potentially providing an opportunity for preservation of islet cell function and natural insulin production.
Thesaurus Terms: "adverse Effects; Alleles; Allelomorphs; Assay; Au Element; Autoantibodies; Autoimmune; Autoimmune Process; Autoimmune Status; Autoimmunity; Beta Cell; Bioassay; Biologic Assays; Biological; Biological Assay; Biological Preservation; Blood Sample; Blood Specimen; Cd8; Cd8b; Cd8b1; Cd8b1 Gene; Cell Communication And Signaling; Cell Function; Cell Process; Cell Signaling; Cell Physiology; Cells; Cellular Function; Cellular Physiology; Cellular Process; Dna Sequence Rearrangement; Data; 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; Diagnosis; Diagnostic; Disease; Disorder; Early Treatment; Event; Expression Profiling; Expression Signature; Frequencies (Time Pattern); Frequency; Gastrointestinal Tract, Pancreas; Genes, T-Cell Receptor; Goals; Gold; Humulin R; Idd; Iddm; Immune; Immune Diseases; Immune Disorders; Immune Dysfunction; Immune System Diseases; Immune System Disorder; Immune Tolerance; Immunologic Diseases; Immunologic Tolerance; Immunological Diseases; Individual; Insulin; Insulin (Ox), 8a-L-Threonine-10a-L-Isoleucine-30b-L-Threonine-; Insulin Cell; Insulin Secreting Cell; Insulin, Regular; Insulin-Dependent Diabetes Mellitus; Intracellular Communication And Signaling; Islet Cell; Lyt3; Legal Patent; Mhc Receptor; Major Histocompatibility Complex Receptor; Measures; Memory; Methods; Molecular; Molecular Fingerprinting; Molecular Profiling; Novolin R; Pancreas; Pancreatic; Patents; Patients; Pattern; Pharmaceutical Agent; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Phase; Preservation, Biologic; Preservation, Biological; Process; Production; Quality Control; Rearrangement; Receptor Protein; Receptors, Antigen, T-Cell; Relative; Relative (Related Person); Research Design; Severities; Signal Transduction; Signal Transduction Systems; Signaling; Staging; Study Type; Subcellular Process; Symptoms; T Memory Cell; T-Cell Receptor; T-Cell Receptor Genes; T1 Diabetes; T1d; T1dm; Tcr Genes; Technology; Time; Treatment Side Effects; Type 1 Diabetes; Variant; Variation; Autoimmune Antibody; Biological Signal Transduction; Biomarker; Blood Glucose Regulation; Case Control; Design; Designing; Disease/Disorder; Glucose Control; Glucose Homeostasis; Glucose Regulation; High Risk; Immune System Tolerance; Immune Unresponsiveness; Immunological Paralysis; Insulin Dependent Diabetes; Insulin Dependent Diabetes Mellitus Onset; Internal Control; Juvenile Diabetes; Juvenile Diabetes Mellitus; Ketosis Prone Diabetes; Memory T Lymphocyte; Molecuar Profile; Molecular Signature; Preservation; Public Health Relevance; Receptor; Self Reactive Antibody; Self Recognition (Immune); Side Effect; Study Design; Therapy Adverse Effect; Tool; Treatment Adverse Effect; Type I Diabetes"
