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Immunological Basis of Autoimmune Addison's Disease in a Novel Canine Model System

新型犬模型系统中自身免疫阿狄森氏病的免疫学基础

基本信息

批准号：
10310454
负责人：
Steven Gene Friedenberg
金额：
$ 13.03万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10310454
关键词：
Addison&apos s disease Adrenal Cortex Adrenal Glands Affect Animal Disease Models Animal Model Animals Antibodies Antigen-Presenting Cells Antigens Autoantibodies Autoantigens Autoimmune Autoimmune Diseases Bacteria Biological Assay Biological Models Bone Density CD4 Positive T Lymphocytes Canis familiaris Cell Line Cell Proliferation Cells Cellular biology Chronic Clinical Clinical Trials Data Development Disease Electrolytes Endocrine System Diseases Enzymes Escherichia coli Exposure to Fostering Funding Future Genes Goals Homeostasis Hormones Human Hybridomas Hypotensives Immune System Diseases Immune mediated destruction Immune response Immunoglobulin Class Switching Immunologics Immunology Immunotherapy Impairment Individual Interferon Type II Interferons Interleukin-2 Lead Learning Life Lymphocyte MHC Class II Genes Measures Mediating Medical Genetics Methods Minnesota Molecular Mus Onset of illness Patients Peptides Population Process Proteins Research Role Shock Sleep Disorders Stains Steroids System T-Cell Receptor T-Lymphocyte Techniques Testing Therapeutic Training Universities Vomiting Work antigen-specific T cells autoreactive T cell autoreactivity base cDNA Library canine model cytokine design high risk insight lipid metabolism next generation novel novel therapeutics protein aminoacid sequence response tool training opportunity translational scientist

项目摘要

Project Summary/Abstract Autoimmune Addison’s Disease (AAD) is a life-threatening endocrine disorder caused by the immune- mediated destruction of the adrenal cortex. Affected individuals lack key hormones that are critical for normal homeostasis. Because of this, patients with AAD are at high risk of developing a potentially deadly adrenal crisis characterized by hypotensive shock, vomiting, and life-threatening electrolyte abnormalities. Limited progress has been made over the past half-century in developing new therapies for AAD, in part because there is no actively studied animal model for the disease. Fortunately, dogs provide an opportunity for this very purpose. The disease is naturally occurring in both humans and dogs, and shares similar clinical, genetic, and immunologic underpinnings in both species. The goal of this study is to lay the groundwork for a canine model system to study AAD by characterizing the antigen-specific T cells that trigger the disease and determining the peptide sequences recognized by these T cells. Specifically, we will test the hypothesis that AAD is triggered by IFN-g- producing CD4+ T cells that are activated by peptides derived from steroid-producing enzymes in the adrenal cortex. Once we have identified and characterized these key players involved in triggering the immune system dysfunction in AAD, we can begin to develop approaches that manipulate or downregulate the aberrant immune response. Ultimately, we expect to use this canine model system to drive advances in our understanding of AAD and to foster the development of novel immunotherapies for humans. The work proposed in this application will be conducted at the renowned Center for Immunology at the University of Minnesota, and will provide a critical training opportunity in T cell biology, autoimmune disorders, and the benchtop methods required to study these topics comprehensively.

项目总结/文摘