Addressing the Biology of Health Disparities by Targeting Geographical Ancestry-driven Variants of Immunity

在美国的种族群体中，非裔美国人的生活水平仍然是最低的 预期癌症死亡率和最高总体癌症死亡率(包括结直肠癌、乳腺癌和前列腺癌 癌症)、婴儿死亡率、哮喘和心脏代谢性疾病(包括心脏病、 高血压和肥胖症)。复杂的疾病和环境侮辱都会引发和/或 通过个体免疫和对治疗剂的不同反应来颠覆宿主炎症 在一定程度上是由基因变异决定的。对个体的精确诊断和预后 患者的反应依赖于在之前、期间和/或评估已知疾病和免疫标记物 治疗后。这项提案将审问Under的功能效应和可药性。 研究了人的基因组中与免疫和药物反应相关的基因变异 非洲血统(AAS)。免疫基因变异在AA中最常见，预计 可药物将被工程改造成不同地理血统的细胞系，并对 在体外和/或体内的功能效应和在硅胶中模拟以预测结构的变化 野生型蛋白质和可能的变异药物相互作用。筛选化合物的新方法 具有治疗潜力的将被开发并用于筛查。候选铅化合物 然后将在体外和/或体内进行验证、优化和测试。这个项目有潜力 1)建立与祖先相关的宿主免疫作为复合体的一个贡献生物学参数 疾病差异；2)通过发现新参与者和 炎症机制及其在复杂疾病中的作用；以及，3)可能导致 开发有效的治疗方法以解决健康差距问题。

Among ethnic groups in the US, African Americans continue to display the lowest life expectancy and highest overall rates of cancer deaths (including colorectal, breast and prostate cancers), infant mortality, asthma, and cardiometabolic diseases (including heart disease, hypertension and obesity). Complex diseases and environmental insults all invoke and/or subvert host inflammation, with individual immune and variable responses to therapeutic agents being dictated in part by genetic variants. Precision diagnoses and prognoses of individual patient responses rely on assessing known disease and immune markers before, during and/or after treatment. This proposal will interrogate the functional effects and druggablity of under- studied gene variants related to immune and drug response within the genome of individuals of African ancestry (AAs). Immune gene variants most common among AAs and predicted to be druggable will be engineered into cells lines of different geographical ancestry and evaluated for functional effects in vitro and/or in vivo and modeled in silico to predict structural changes to the wild type proteins and possible variant-drug interactions. Novel assays to screen for compounds with therapeutic potential will be developed and used for screening. Lead compound candidates will then be validated, optimized and tested in vitro and/or in vivo. This project has the potential to 1) establish ancestry-related host immunity as a contributing biological parameter of complex disease disparities; 2) fill in critical knowledge gaps by identifying novel players and mechanisms of inflammation and their role in complex disease; and, 3) possibly lead to the development of effective therapies to address health disparities.