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：
10273703
负责人：
Kevin Sean Kimbro
金额：
$ 70.22万
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 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10273703
关键词：
Address African African American 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 Outcome Participant Pattern Predisposition Progress Reports Proteins Public Health Research Role Socioeconomic Factors Structure Temperature Testing The Sun Therapeutic Therapeutic Agents Untranslated RNA Variant base cancer health disparity disease disparity effective therapy ethnic minority population genetic variant health 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.

在美国的族裔中，非裔美国人继续表现出最低的生活预期和最高的癌症死亡率（包括结直肠癌，乳房和前列腺癌症），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）。复杂的疾病和环境侮辱都调用和/或颠覆宿主炎症，对治疗剂具有单独的免疫和可变反应部分由遗传变异决定。精确诊断和预后患者的反应依赖于评估已知疾病和免疫标记之前，期间和/或治疗后。该提案将询问不足的功能效应和药品研究了与个体个体基因组中与免疫和药物反应有关的基因变异非洲血统（AAS）。免疫基因变体在AAS中最常见，预计为可吸毒将设计为不同地理祖先的细胞系，并评估在体外和/或体内的功能效应，并在硅中进行建模，以预测结构性变化野生型蛋白质和可能的变体相互作用。筛选化合物的新颖测定具有治疗潜力并将用于筛查。铅复合候选人然后将在体外和/或体内进行验证，优化和测试。这个项目有潜力到1）建立与祖先相关的宿主免疫作为复合物的生物学参数疾病差异； 2）通过识别新颖玩家和炎症机制及其在复杂疾病中的作用； 3）可能导致开发有效疗法以解决健康差异。