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

通过针对地理血统驱动的免疫变异来解决健康差异的生物学问题

基本信息

批准号：
10491138
负责人：
Kevin Sean Kimbro
金额：
$ 67.91万
依托单位：
NORTH CAROLINA CENTRAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2023-07-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10491138
关键词：
Address African American population African ancestry Aftercare American Association of Cancer Research Amino Acid Sequence Asthma Biological Biological Assay Biological Factors Biology COVID-19 Cancer Death Rates Cancer Patient Cardiometabolic Disease Cardiovascular Diseases Cell Line Cells Clinical Trials Code Colorectal Cancer Communicable Diseases Complex Development Diagnosis Disease Disease Marker Drug Interactions Engineering Environment Ethnic group European Evolution Family Food Supply Foundations Genes Genetic Genome Geography Heart Diseases Human Hypertension Immune Immune response Immunity Immunologic Markers Immunotherapeutic agent In Vitro Indigenous Individual Infant Mortality Inflammation Knowledge Lead Life Expectancy Link Malignant Neoplasms Malignant neoplasm of prostate Medical Mutation Neurodegenerative Disorders Obesity Participant Pattern Predisposition Prognosis Progress Reports Proteins Public Health Research Role Socioeconomic Factors Temperature Testing The Sun Therapeutic Therapeutic Agents Untranslated RNA Variant base cancer health disparity disease disparity effective therapy ethnic minority genetic variant health disparity health outcome disparity in silico in vivo in vivo Model individual patient innovation insight knowledge base malignant breast neoplasm microbial molecular targeted therapies novel pathogen patient response population based pressure racial minority response screening

项目摘要

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.

在美国的族裔群体中，非裔美国人的生活水平仍然最低癌症死亡率（包括结直肠癌、乳腺癌和前列腺癌）的预期和最高总体死亡率癌症）、婴儿死亡率、哮喘和心脏代谢疾病（包括心脏病、高血压和肥胖）。复杂的疾病和环境侵害都会引发和/或通过个体免疫和对治疗药物的不同反应来破坏宿主炎症部分由遗传变异决定。个体的精确诊断和预后患者的反应依赖于在之前、期间和/或之前评估已知疾病和免疫标记物治疗后。该提案将探讨以下药物的功能作用和成药性：研究了个体基因组内与免疫和药物反应相关的基因变异非洲血统（AA）。免疫基因变异在 AA 中最常见，预计 druggable 将被工程化到不同地理祖先的细胞系中并进行评估体外和/或体内的功能效应，并在计算机中建模以预测结构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药物将被开发并用于筛选。先导化合物候选者然后将在体外和/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物的一个贡献生物学参数疾病差异； 2）通过识别新玩家来填补关键知识空白炎症机制及其在复杂疾病中的作用；并且，3）可能导致开发有效的疗法来解决健康差异。