Document text
Principal Investigator: SALLY Choate KENT
Organization: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
Fiscal Year: 2024
Award: $751,132
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY/ABSTRACT (30 lines or less)
The premise for the proposed research stems from precedence in other diseases, such as cancer,
cardiovascular, neurodegenerative, and most relevant to the current proposal, autoimmune diseases, in which
extracellular vesicles (EVs) play a role in the pathophysiology and are important biomarkers for early detection.
However, in human type 1 diabetes (T1D), little is known concerning EVs in cellular communication. Our overall
hypothesis is that autocrine-paracrine interactions, mediated through EVs, between the islets and islet-infiltrating
immune cells in the pancreas contribute to the development and progression of T1D. Our specific aims are: 1)
to assess the functional impact of islet-infiltrating T-cell derived EVs (T-EV) from T1D and autoantibody+ (Aab+)
donors on islet health and on distinct immune cell populations; 2) to investigate the contribution of stressed or
T1D islet-derived EVs (I-EV) on immune cell phenotype and islet health; and 3) to decipher the differential protein
cargo in T-EV and I-EV from T1D and Aab+ donors. To address these aims, we have assembled a team of
investigators with highly relevant expertise, techniques and unique resources of cell lines and tissue samples.
From 36 human tissue donors with T1D or Aab positivity, we have >600 T cell lines grown directly from the
individual islets of pancreata. We have the expertise and technical ability to isolate EV from islets (I-EV) and
from islet-infiltrating T cell lines (T-EV) from T1D donors. Our preliminary data indicates I-EV and T-EV have
both paracrine and autocrine effects on islet health and immune cell phenotype. Our Research Plan is to
generate T-EV and I-EV from donors with T1D of distinct durations or positivity for islet autoantibodies, to
evaluate their effects on islet health and immune cell function, and to determine the uniquely packaged protein
cargo from these EVs whose molecular composition reflects the pathophysiologic state of the disseminating cell.
These studies will yield important information concerning the communication between immune cell populations
and islets via EVs in the pathogenesis of T1D, and potential biomarkers or therapeutic targets for T1D.
Terms: <Address><Adult-Onset Diabetes Mellitus><Affect><Autoantibodies><Autoantigens><Autocrine Systems><Autoimmune><Autoimmune Diseases><Autologous><Autologous Antigens><B9 endocrine pancreas><Beta Cell><Blood monocyte><Body Tissues><Brittle Diabetes Mellitus><CD8><CD8B><CD8B1><CD8B1 gene><Cancers><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular Pathology><Cardiovascular system><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Function><Cell Interaction><Cell Isolation><Cell Line><Cell Physiology><Cell Process><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cell to Cell Communication and Signaling><Cell-Cell Signaling><Cell-to-Cell Interaction><CellLine><Cells><Cellular Function><Cellular Physiology><Cellular Process><Characteristics><Communication><Data><Dendritic Cells><Development><Diabetes Mellitus><Disease><Disorder><Dysfunction><Endocrine Pancreas><Environment><Family><Functional disorder><Goals><Hand><Health><Heart Vascular><Human><Humulin R><IDDM><Immune><Immune infiltrates><Immunes><Individual><Inflammation><Inflammatory><Innate Immune System><Insulin><Insulin Cell><Insulin Secreting Cell><Insulin-Dependent Diabetes Mellitus><Intracellular Communication and Signaling><Investigators><Islands of Langerhans><Islets of Langerhans><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Ketosis-Resistant Diabetes Mellitus><Knowledge><LYT3><Lytotoxicity><Malignant Neoplasms><Malignant Tumor><Marrow monocyte><Maturity-Onset Diabetes Mellitus><Mediating><Mediator><Membrane><Modern Man><Molecular><NIDDK><NIDDM><National Institute of Diabetes and Digestive and Kidney Diseases><Nerve Degeneration><Nesidioblasts><Neuron Degeneration><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Novolin R><Organ><Organ Donor><Pancreas><Pancreatic><Pancreatic Islets><Pars endocrina pancreatis><Pathogenesis><Patients><Peripheral><Phenotype><Physiopathology><Population><Proteins><Regular Insulin><Research><Research Personnel><Research Resources><Researchers><Resources><Role><STEM research><Self-Antigens><Signal Transduction><Signal Transduction Systems><Signaling><Slice><Slow-Onset Diabetes Mellitus><Source><Spleen><Spleen Reticuloendothelial System><Stable Diabetes Mellitus><Strains Cell Lines><Stress><Subcellular Process><Sudden-Onset Diabetes Mellitus><T cell infiltration><T cell response><T-Cell Activation><T-Cells><T-Lymphocyte><T1 DM><T1 diabetes><T1D><T1DM><T2 DM><T2D><T2DM><Techniques><Testing><Tissue Donors><Tissue Sample><Tissues><Type 1 Diabetes Mellitus><Type 1 diabetes><Type 2 Diabetes Mellitus><Type 2 diabetes><Type I Diabetes Mellitus><Type II Diabetes Mellitus><Type II diabetes><Veiled Cells><Vesicle><activate T cells><adult onset diabetes><autocrine><autoimmune antibody><autoimmune condition><autoimmune disorder><autoimmunity disease><autoreactive antibody><biological signal transduction><cell sorting><cell type><circulatory system><cultured cell line><cytokine><cytotoxic><cytotoxicity><developmental><diabetes><diabetes pathogenesis><early biomarkers><early detection biomarkers><early detection markers><extracellular vesicles><hands><human tissue><immune cell infiltrate><inflammatory environment><inflammatory milieu><insight><insulin dependent diabetes><insulin dependent type 1><intercellular communication><islet><islet autoantibody><islet cell antibody><islet progenitor><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><ketosis resistant diabetes><malignancy><maturity onset diabetes><membrane structure><monocyte><neoplasm/cancer><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neurological pathology><neuronal degeneration><novel><paracrine><pathophysiology><potential biological marker><potential biomarker><science, technology, engineering and math research><science, technology, engineering and mathematics research><self reactive antibody><social role><therapeutic target><thymus derived lymphocyte><type 2 DM><type I diabetes><type II DM><type one diabetes><type two diabetes><β-cell><β-cells><βCell>