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：
10536617
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10536617
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 Breeding 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 Genetic Goals Heritability Homeostasis Hormones Human Hybridomas Hypertension Hypotensives Immune System Diseases Immune mediated destruction Immune response Immunoglobulin Class Switching Immunologics Immunology Immunotherapy Impairment Individual Interferon Type II Interferons Interleukin-2 Learning Life Lymphocyte MHC Class II Genes Measures Mediating Methods Minnesota Molecular Mus Onset of illness Patients Peptides Population Process Proteins Research Role Shock Sleep Disorders Sorting Stains Steroids System T-Cell Activation T-Cell Receptor T-Lymphocyte Techniques Testing Therapeutic Training Transfection Universities Vomiting Work antigen-specific T cells autoreactive T cell autoreactivity cDNA Library canine model cytokine design high risk insight lipid metabolism model organism 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.

项目概要/摘要自身免疫性阿狄森氏病（AAD）是一种危及生命的内分泌疾病，由免疫系统引起。受影响的个体缺乏对正常情况至关重要的关键激素。因此，AAD 患者患上潜在致命性肾上腺疾病的风险很高。以低血压休克、呕吐和危及生命的电解质异常为特征的危象。过去半个世纪在开发 AAD 新疗法方面取得了进展，部分原因是目前还没有针对这种疾病进行积极研究的动物模型，幸运的是，狗为此提供了机会。该疾病自然发生在人类和狗身上，并且具有相似的临床、遗传和特征。本研究的目的是为犬类模型奠定基础。通过表征触发疾病的抗原特异性 T 细胞并确定 AAD 的系统来研究 AAD 具体来说，我们将测试 AAD 被触发的假设。产生 IFN-g 的 CD4+ T 细胞被来自类固醇生成酶的肽激活一旦我们确定并表征了参与触发免疫的这些关键参与者。 AAD 中的系统功能障碍，我们可以开始开发操纵或下调异常的方法最终，我们希望利用这种犬类模型系统来推动我们的进步。了解 AAD 并促进人类新型免疫疗法的开发。本申请中提出的方案将在著名的大学免疫学中心进行明尼苏达州，并将提供 T 细胞生物学、自身免疫性疾病和全面研究这些主题所需的台式方法。