Project 2

项目2

• 批准号: 10246845
• 负责人: Jeannine S McCune
• 金额: $ 7.96万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 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/10246845
• 关键词: Affinity; African American; American; Antibodies; Apoptosis; Arsenic; BRCA1 Mutation; Binding; Breast Cancer Risk Factor; Cadmium; Cancer Biology; Cancerous; Carcinogens; Chemoresistance; Color; Contralateral Breast; Data; Development; Discrimination; Drug Kinetics; Drug Stability; ERBB2 gene; Environmental Risk Factor; Epigenetic Process; 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; Prognosis; Proteins; Resistance; Risk; Sensitivity and Specificity; Site; Structure; Testing; Therapeutic; Toxic effect; United States; Woman; Work; Xenograft Model; autism spectrum disorder; black women; cancer initiation; 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; 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-/HER2野生型]经常对化疗耐药，预后较差。 特别是在黑人/非裔美国妇女中。黑人/非洲人TnBC启动的分子机制 美国人和拉丁裔/西班牙裔女性很少被理解。长期以来，人们一直怀疑 营养和接触致癌物可能会增加患乳腺癌的风险。有色人种女性体验 社区和住房中的歧视，导致无法获得健康食品，并增加 接触铅、砷和镉等重金属。基因组印记是一种遗传形式的 表观遗传基因调控，将营养和重金属暴露的差异与糖尿病的终身风险联系起来 肥胖、自闭症、心脏病和癌症。我们推测这种不正常的印记可能与 营养和住房方面的差异与具有侵略性的TNBC生物学有关。在初步数据中，我们调查了KCNK9 (TASK3蛋白)，一种对pH敏感的钾通道蛋白，在大多数(91%)TNBC中高表达 这种情况发生在黑人/非裔美国女性身上。当TASK3过度表达时，会增加线粒体 膜蛋白，抗凋亡，并促进侵略性的TNBC生物学。在这里，我们的目标是开发 选择性/高亲和力TASK3抑制剂。为此，我们为人类建立了一种电子同源模型。 TASK3二聚体。确定了四个潜在的“可用药”交互作用地点。在这个试点项目中，我们的目标是测试 假设TASK3是治疗和预防黑人/非洲人TNBC的可行靶点- 美国和拉丁裔/西班牙裔妇女。AIM 1将进行体外筛选和结构功能优化 铅TASK3抑制剂(Perry，McCune)。目的2将表征药物稳定性和药代动力学。 任务抑制药(Perry、McCune、Sistrunk)。