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）

• 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
• 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

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).

摘要： TNBC [ER-/PR-/HER 2野生型]通常是化疗抗性的并且预后不良， 尤其是黑人/非裔美国妇女。TNBC启动的分子机制在黑人/非洲- 美国和拉丁美洲/西班牙裔妇女知之甚少。长期以来，人们一直怀疑， 营养不良和接触致癌物质可能会增加患乳腺癌的风险。有色人种女性体验 社区和住房方面的歧视导致缺乏获得健康食品的机会， 接触重金属，如铅、砷和镉。基因组印记是一种遗传形式， 表观遗传基因调控将营养和重金属暴露的差异与终身风险联系起来， 肥胖症、自闭症、心脏病和癌症。我们假设异常的印记 营养和住房方面的差距与侵略性TNBC生物学。在初步数据中，我们研究了KCNK 9 （TASK 3蛋白），一种pH敏感性钾通道蛋白，在大多数（91%）TNBC中过表达。 发生在黑人/非裔美国女性身上的当过表达时，TASK 3增加线粒体 膜蛋白，抗肿瘤，并促进侵略性TNBC生物学。在这里，我们的目标是发展 选择性/高亲和力TASK 3抑制剂。为了做到这一点，我们建立了一个计算机同源性模型的人类 TASK 3二聚体。确定了四个潜在的“可用药”相互作用位点。在这个试点项目中，我们旨在测试 假设TASK 3是治疗和预防黑人/非洲人TNBC的可行靶点- 美国和拉丁/西班牙裔妇女。目标1将进行体外筛选和结构功能优化 TASK 3抑制剂（佩里，McCune）。目的2将表征药物稳定性和药代动力学 任务抑制剂（佩里，McCune，Sistrunk）。