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

部落成员自身免疫的分子表型：协助精准医学和部落学生培训

• 批准号: 10005381
• 负责人: JUDITH A JAMES
• 金额: $ 39.1万
• 依托单位: CHEROKEE NATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-12 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005381
• 关键词: Address; Age; Aging; American Indians; Antigens; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Award; Big Data Methods; Biological Markers; Catchment Area; Cherokee Indian; Cherokee Nation, Oklahoma; Chronic; Classification; Clinic; Clinical; Clinical Data; Clinical Immunology; Clinical Research; Collection; Computerized Medical Record; County; Data; Data Analytics; Databases; Degenerative polyarthritis; Diagnosis; Disease; Disease Pathway; Enrollment; Evaluation; Expression Profiling; Family-Based Registry; Finding by Cause; Foundations; Gene Expression; Geography; Health; Health care facility; Health system; Healthcare; Human Resources; Immune; Immunologics; Immunophenotyping; Inequality; Investigation; Joints; Leadership; Length; Life Expectancy; Liver diseases; Lupus; Measures; Medical; Mentors; Methylation; Mitochondria; Molecular; Morbidity - disease rate; Myositis; Native American Research Center for Health; Oklahoma; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Phenotype; Physician Assistants; Physicians; Plasma; Population; Precipitin Tests; Principal Investigator; Proteomics; Research; Research Infrastructure; Research Personnel; Resources; Rheumatism; Rheumatoid Arthritis; Rheumatology; Scientist; Serological; Services; Specificity; Statistical Algorithm; Students; Systemic Lupus Erythematosus; Systemic Scleroderma; Systems Biology; Talents; Testing; Training; Training Programs; Training and Infrastructure; Tribes; Visualization; Work; base; biobank; career; chemokine; classification algorithm; cohort; cytokine; data management; disability-adjusted life years; health inequalities; improved; innovation; laboratory equipment; meetings; molecular phenotype; mortality; patient population; peripheral blood; precision medicine; programs; racial and ethnic; receptor; recruit; repository; rural counties; sample collection; student training; success; telomere; tribal member

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.

项目摘要： 美洲印第安人（AIS）拥有一些最短的寿命，地理不平等现象更大 像切诺基国家集水区的农村县宣布。这些发现的原因 是多因素的，在许多慢性健康状况中受到较差的结果的影响，例如 风湿病。不幸的是，美国部落成员在风湿病中的一些最高 这个国家，包括全身性红斑狼疮（SLE），类风湿关节炎（RA）和 全身性硬化。为了帮助解决这些健康不平等，该项目试图了解分子 俄克拉荷马州部落患者加速衰老的免疫表型和潜在的机制以更好 告知诊断和治疗。 OMRF，OUHSC和Cherokee Nation一起组装了 风湿性疾病研究和基础设施对于这个提出的项目的成功至关重要， 作为来自454名AI SLE患者的样品和相关临床数据的收集，190名AI RA患者和300名AI 对照，以及其他种族/种族背景的其他患者和对照。部落 Narch风湿病诊所已招募273名部落风湿病患者。联合发现 日期包括：部落种群具有风湿病的重叠特征很常见（没有 满足标准分类标准），美国不存在特定疾病的自身抗体标记 印度患者，多达41％的AI SLE患者具有高浓度的先前未识别 自动抗体。一些未知的SLE特异性针对线粒体或特异性肌炎 抗原。基于这些结果，该应用程序汇集了三种尖端的科学方法， 精密医学/深度分子表型，大数据分析/可视化和分子机制 加速衰老，以识别AI风湿病患者的失调途径。 我们将通过以下目的解决相关的假设：（1）综合 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 - 与匹配的对照相比，美洲印第安人患有SLE或RA患者的相关变化 独特而重要的疾病途径，富含AI自身免疫性。 （2）评估美洲印第安人 风湿性自身免疫性疾病患者，用于加速衰老的分子证据。我们的关键人员有 指导了20多名美洲印第安学生获得高级学位和学术，医疗和部落服务 作为医生，医师助理和科学家的职业。该项目为部落提供了额外的培训 学生，最初的三个已经确定。临床研究，数据管理，数据分析的培训， 将向部落学生和研究人员提供临床免疫学和精密医学 专注于识别分子信息以选择和完善理性的定向疗法以改善AI 风湿病患者的结局。