Molecular Phenotyping of Autoimmunity in Tribal Members: Aiding Precision Medicine and Tribal Student Training

项目总结： 美洲印第安人(Ais)的预期寿命最短，地域不平等更甚。 在像切罗基民族集水区这样的农村县很明显。这些发现的原因是什么？ 是多因素的，并受到许多慢性健康状况较差结果的影响，例如 风湿病。不幸的是，美国部落成员的风湿病发病率在 包括系统性红斑狼疮(SLE)、类风湿性关节炎(RA)等疾病，以及 系统性硬化症。为了帮助解决这些健康不平等问题，这个项目试图了解 俄克拉荷马州部落患者加速衰老的免疫学表型和潜在机制 告知诊断和治疗。OMRF、OUHSC和切诺基民族一起聚集在一起 风湿病研究和基础设施对这一拟议项目的成功至关重要，例如 收集了454例AI型SLE患者、190例AI型RA患者和300例AI型患者的样本和相关临床数据 另外还有数千名患者和其他种族/族裔背景的对照人员。部落 NARCH风湿病诊所又招募了273名部落风湿病患者。联合调查结果 日期包括：部落人口通常有风湿病的重叠特征(没有 符合标准分类标准)，疾病特异性自身抗体标记物在美国不存在 印度患者，高达41%的AI SLE患者有高浓度的以前未确认的 自身抗体。一些未知的SLE特异性针对线粒体或肌炎特异性 抗原。基于这些结果，这一应用程序汇集了三种尖端科学方法， 精确医学/深分子表型、大数据分析/可视化和分子机制 加速衰老，以确定AI风湿病患者的失调途径。 我们将通过以下目标解决相关的假设：(1)执行全面的 自身免疫性疾病的血清学、基因表达和细胞证据的分子表型评估- 与匹配对照组相比，美国印第安人SLE或RA患者的相关变化 在AI自身免疫中丰富的独特而重要的疾病途径。(2)评价美国印第安人 风湿性自身免疫性疾病患者加速衰老的分子证据。我们的主要人员已经 指导了20多名美国印第安人学生获得高级学位以及学术、医疗和部落服务 从事内科医生、医师助理和科学家的职业。该项目为部落提供额外的培训 学生，最初的三个已经确定。临床研究、数据管理、数据分析、 将为部落学生和调查人员提供临床免疫学和精准医学， 专注于识别分子信息，以选择和提炼合理的、定向的疗法来改善人工智能 风湿病患者的预后。

Project Summary: American Indians (AIs) have some of the shortest life-expectancies with geographic inequalities even more pronounced in rural counties like those in the Cherokee Nation catchment area. The causes for these findings are multi-factorial and are impacted by poorer outcomes in many chronic health conditions, such as the rheumatic diseases. Unfortunately, US tribal members have some of the highest rates of rheumatic disease in the nation, including diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis. To help address these health inequalities, this project seeks to understand the molecular immunologic phenotypes and potential mechanisms of accelerated aging in Oklahoma tribal patients to better inform diagnosis and treatments. Together, OMRF, OUHSC and the Cherokee Nation have assembled rheumatic disease research and infrastructure which are critical for the success of this proposed project, such as collections of samples and associated clinical data from 454 AI SLE patients, 190 AI RA patients and 300 AI controls, as well as thousands of additional patients and controls of other racial/ethnic backgrounds. Tribal NARCH rheumatology clinics have enrolled 273 additional tribal rheumatic disease patients. Joint findings to date include: it is common for tribal populations to have overlapping features of rheumatic disease (without meeting standard classification criteria), disease-specific autoantibody markers are not present in American Indian patients, and up to 41% of AI SLE patients have high concentrations of previously unidentified autoantibodies. Some unknown SLE specificities are directed against mitochondrial or myositis-specific antigens. Based upon these results, this application brings together three cutting-edge scientific approaches, precision medicine/deep molecular phenotyping, big data analytics/visualization and molecular mechanisms of accelerated aging, to identify dysregulated pathways in AI rheumatic disease patients. We will address the associated hypotheses through the following aims: (1) Perform a comprehensive molecular phenotypic evaluation of serologic, gene expression and cellular evidence of autoimmune disease- associated changes in American Indian patients with SLE or RA compared to matched controls to identify unique and important disease pathways which are enriched in AI autoimmunity. (2) Evaluate American Indian rheumatic autoimmune disease patients for molecular evidence of accelerated aging. Our key personnel have mentored over 20 American Indian students to advanced degrees and academic, medical and tribal service careers as physicians, physician assistants, and scientists. This project provides additional training to tribal students, with the initial three already identified. Training in clinical research, data management, data analytics, clinical immunology and precision medicine will be provided to the tribal students and investigators, which focuses on identifying molecular information to select and refine rational, directed therapies to improve AI rheumatic disease patient outcomes.