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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：
10830527
负责人：
Steven Gene Friedenberg
金额：
$ 7.29万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-12-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10830527
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.

项目摘要/摘要自身免疫性爱迪生病(AAD)是一种由免疫缺陷引起的危及生命的内分泌疾病。中介破坏了肾上腺皮质。受影响的人缺乏对正常生活至关重要的关键激素动态平衡。正因为如此，AAD患者罹患潜在致命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。有限在过去的半个世纪里，在开发治疗AAD的新疗法方面取得了进展，部分原因是目前还没有对这种疾病进行积极研究的动物模型。幸运的是，狗为这一点提供了一个机会目的。这种疾病自然发生在人和狗身上，具有相似的临床、遗传和这两个物种的免疫学基础。本研究的目的是为建立犬模型奠定基础。通过鉴定触发疾病的抗原特异性T细胞并确定AAD的这些T细胞识别的多肽序列。具体地说，我们将测试AAD被触发的假设通过产生干扰素-g的CD4+T细胞，这些细胞被来自类固醇产生酶的多肽激活肾上腺皮质。一旦我们确定并表征了这些与触发免疫有关的关键角色在AAD中，我们可以开始开发操纵或下调异常的方法免疫反应。最终，我们希望使用这个犬类模型系统来推动我们的了解AAD，并促进人类新型免疫疗法的开发。这项工作在本申请中提出的建议将在著名的华盛顿大学免疫学中心进行并将提供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。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Canine junctional epidermolysis bullosa due to a novel mutation in LAMA3 with severe upper respiratory involvement.

DOI：
10.1111/vde.12972
发表时间：
2021-08
期刊：
Veterinary dermatology
影响因子：
1.4
作者：
Herrmann I;Linder KE;Meurs KM;Friedenberg SG;Cullen J;Olby N;Bizikova P
通讯作者：
Bizikova P

Congenital muscular dystrophy in a dog with a LAMA2 gene deletion.

DOI：
10.1111/jvim.16330
发表时间：
2022-01
期刊：
Journal of veterinary internal medicine
影响因子：
2.6
作者：
Shelton GD;Minor KM;Thomovsky S;Guo LT;Friedenberg SG;Cullen JN;Mickelson JR
通讯作者：
Mickelson JR

An EHPB1L1 Nonsense Mutation Associated with Congenital Dyserythropoietic Anemia and Polymyopathy in Labrador Retriever Littermates.

DOI：
10.3390/genes13081427
发表时间：
2022-08-11
期刊：
Genes
影响因子：
3.5
作者：
通讯作者：

Red cell distribution width is a predictor of all-cause mortality in hospitalized dogs.

DOI：
10.1111/vec.13109
发表时间：
2022-01
期刊：
JOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE
影响因子：
1.3
作者：
Ludwik, Tasia M.;Heinrich, Daniel A.;Rendahl, Aaron;Friedenberg, Steven G.
通讯作者：
Friedenberg, Steven G.

A novel mutation of the CLCN1 gene in a cat with myotonia congenita: Diagnosis and treatment.

DOI：
10.1111/jvim.16471
发表时间：
2022-07
期刊：
JOURNAL OF VETERINARY INTERNAL MEDICINE
影响因子：
2.6
作者：
Woelfel, Christian;Meurs, Kathryn;Friedenberg, Steven;DeBruyne, Nicole;Olby, Natasha J.
通讯作者：
Olby, Natasha J.