2/2 Drug Development and Capacity Building: A UCR/CoH-CCC Partnership (Pilot Project 2)

2/2 药物开发和能力建设：UCR/CoH-CCC 合作伙伴关系（试点项目 2）

基本信息

批准号：
10006588
负责人：
John Jefferson Perry
金额：
$ 11.14万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-02 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10006588
关键词：
Affinity African American American Antibodies Apoptosis Arsenic BRCA1 Mutation Binding Breast Cancer Risk Factor Cadmium Cancer Biology Cancerous Carcinogens Color Contralateral Breast Data Development Discrimination Drug Kinetics Drug Stability ERBB2 gene Environmental Risk Factor Epigenetic Process Estrogen receptor positive European Event Exposure to Frequencies Gene Expression Regulation Genetic Risk Genomic Imprinting Goals Health Food Heart Diseases Heavy Metals Hispanics Homology Modeling Housing Human In Vitro Individual Inherited Latina Lead Link Malignant Neoplasms Mammary Gland Parenchyma Metal exposure Mitochondrial Membrane Protein Modeling Molecular Natural Products Neighborhoods Neoplasm Metastasis Pharmaceutical Preparations Pilot Projects Potassium Channel Prevention Proteins Resistance Risk Sensitivity and Specificity Site Structure Testing Therapeutic Toxic effect United States Woman Work Xenograft Model autism spectrum disorder cancer initiation chemotherapy child bearing dimer drug development drug discovery early pregnancy ethnic difference experience gene product imprint in silico inhibitor/antagonist lead optimization malignant breast neoplasm men nutrition obesity risk outcome forecast overexpression racial difference sanshool screening therapeutic development therapeutic target triple-negative invasive breast carcinoma

项目摘要

Abstract: TNBC [ER-/PR-/HER2 wild-type] is frequently chemotherapy-resistant and carries a poor prognosis, particularly in Black/African American women. The molecular mechanisms of TNBC-initiation in Black/African- American and Latina/Hispanic women are poorly understood. It has been long suspected that disparities in nutrition and exposure to carcinogens may increase breast cancer-risk. Women-of-color experience discrimination in neighborhoods and housing that result in lack of access to healthy foods and increased exposure to heavy metals such as lead, arsenic, and cadmium. Genomic imprinting is an inherited form of epigenetic gene regulation that links disparities in nutrition and heavy metal exposure to lifelong risk for obesity, autism, heart disease, and cancer. We hypothesized that that abnormal imprinting might link disparities in nutrition and housing with aggressive TNBC biology. In preliminary data, we investigated KCNK9 (TASK3 protein), a pH-sensitive potassium channel protein that is overexpressed in a majority (91%) of TNBC that occur in Black/African-American women. When overexpressed, TASK3 increases mitochondrial membrane protein, apoptosis-resistance, and promotes aggressive TNBC biology. Here we aim to develop selective/high affinity TASK3 inhibitors. To do this we established an in silico homology model for the human TASK3 dimer. Four potential “druggable” interaction sites were identified. In this pilot project we aim to test the hypothesis that TASK3 is a viable target for both treatment and prevention of TNBC in Black/African- American and Latina/Hispanic women. Aim 1 will perform in vitro screening and structure-function optimization of lead TASK3 inhibitors (Perry, McCune). Aim 2 will characterize the drug stability and pharmacokinetics of TASK inhibitors (Perry, McCune, Sistrunk).

抽象的： TNBC [er-/pr-/her2野生型]经常耐化学疗法，预后不良，特别是在黑人/非洲裔美国妇女中。黑人/非洲 - 非洲 - 非洲 - 美国和拉丁裔/西班牙裔妇女的理解很差。长期以来一直怀疑分配营养和暴露于致癌物可能会增加乳腺癌风险。颜色的女性经验在社区和住房中的歧视，导致无法获得健康食品并增加暴露于铅，砷和镉等重金属。基因组印迹是一种继承的形式表观遗传基因调节将营养和重金属差异与终身风险联系起来肥胖，自闭症，心脏病和癌症。我们假设异常印记可能会联系起来具有侵略性TNBC生物学的营养和住房差异。在初步数据中，我们研究了KCNK9 （Task3蛋白），一种pH敏感的钾通道蛋白，在大多数（91％）的TNBC中过表达这发生在黑人/非裔美国妇女中。当过表达时，任务3会增加线粒体膜蛋白，抗凋亡 - 抗性，并促进侵袭性TNBC生物学。在这里我们旨在发展选择性/高亲和力任务3抑制剂。为此，我们为人类建立了一个硅同源性模型 task3二聚体。确定了四个潜在的“可药”相互作用位点。在这个试点项目中，我们旨在测试假设Task3是黑人/非洲 - 非洲的治疗和预防TNBC的可行目标美国和拉丁裔/西班牙裔妇女。 AIM 1将在体外筛查和结构功能优化中执行铅任务3抑制剂（Perry，McCune）。 AIM 2将表征药物稳定性和药代动力学任务抑制剂（Perry，McCune，Sistrunk）。