Pilot Project 1

试点项目1

基本信息

批准号：
9246681
负责人：
Jennifer Ann Freedman
金额：
$ 15.61万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-16 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9246681
关键词：
5&apos -AMP-activated protein kinase Acetates Address Affect African American Aftercare Age Alternative Splicing Androgen Antagonists Androgen Receptor Androgens Antiandrogen Therapy Automobile Driving Biological Biological Factors Biological Markers Biomanufacturing Biopsy Specimen Cancer Biology Cancer Burden Cancer Center Cellular biology Characteristics Clinical Clinical Trials Collaborations Data Data Set Development Diagnosis Disease Elements Enrollment Event Exhibits Faculty Gene Targeting Genes Genetic Genotype Goals Hormonal Incidence Institutes Institution Joints Laboratories Malignant Neoplasms Malignant neoplasm of prostate Minority Molecular National Cancer Institute North Carolina Nucleic Acid Regulatory Sequences Oligonucleotides Outcome Patients Phenotype Pilot Projects Plasma Play Population Postdoctoral Fellow Precision therapeutics Prevention Prostate-Specific Antigen RNA RNA Splicing Race Receptor Inhibition Receptor Signaling Research Research Institute Research Personnel Research Project Grants Role Signal Transduction Single Nucleotide Polymorphism Spliced Genes Steroids Technology Therapeutic Training Translational Research Tumor Cell Biology Underrepresented Students Universities Variant Whole Blood Work abiraterone anticancer research cancer health disparity cancer risk genomic data health disparity member men mortality novel population based pre-clinical prostate cancer cell prostate cancer model response small molecule small molecule therapeutics social health determinants survival prediction treatment response tumor tumor progression

项目摘要

African Americans (AAs) exhibit higher incidence of and mortality from prostate cancer (PCa) than whites. Although much of the disparate cancer burden can be explained by differences in social determinants of health, a significant portion of this disparity remains after controlling for these factors. The studies proposed here address the urgent need to elucidate the molecular mechanisms underlying the more aggressive PCa biology in AA men, to manipulate these mechanisms for therapeutic application and to determine the importance of these mechanisms for response to current therapeutic strategies. At Duke Cancer Institute (DCI), we have identified novel alternatively spliced genes in AA versus white PCa and have shown that AA variants track with more aggressive cancer invasion characteristics of PCa in AA men. We have also identified novel single nucleotide polymorphisms located in splicing regulatory regions of such genes that associate with PCa risk, aggressiveness and survival. Subsets of these genes are androgen receptor (AR) targets, relevant given the role that AR signaling plays in PCa progression, use of anti-androgen therapy and association of AR signaling with PCa health disparities. In parallel, at North Carolina Central University (NCCU), we have interrogated AMP-activated protein kinase (AMPK) signaling, which operates in a regulatory loop with AR, thus having therapeutic implications for race-related PCa. Using the Bio-manufacturing Research Institute and Technology Enterprise at NCCU, we identified 8 novel small molecule AMPK activators. The proposed work is a joint translational science pilot project to further develop the existing NCCU-DCI partnership, support focused collaboration in cancer research, enhance cancer research at NCCU and cancer health disparities research at DCI and support the development of 2 junior faculty and a minority postdoc. Our objectives are to 1) interrogate and modulate race-related AR target splice variants and 2) elucidate genetic factors important for response to anti-androgen therapy among and between racial groups. Specifically, we aim to 1) define the biological significance of modulating the levels of race-related AR target RNA splice variants on PCa cell biology, using novel RNA therapeutics and small molecules, 2) define the biological significance of cis- acting splicing elements of alternatively spliced AR target genes in AA PCa to alternative RNA splicing events and AA race-related PCa cell biology, by expressing variants containing the AA or white genotype and assessing alterations on splicing and PCa cell biology and 3) define the biological factors related to alternative RNA splicing events and AMPK signaling that are critical for response to the anti-androgen, Abiraterone Acetate, among and between racial groups, performing association analyses of correlatives with clinical parameters in a clinical trial. The rationale for and impact of the work proposed here is that it will reveal molecular mechanisms that can pave the way toward development of novel precision biomarkers for PCa risk, aggressiveness, therapeutic response and/or survival prediction among minorities as well as precision therapeutics for PCa disparities.

非洲裔美国人（AAS）表现出比前列腺癌（PCA）的发病率更高的白人。尽管许多不同的癌症负担可以通过社会决定因素的差异来解释在控制这些因素之后，健康差异的很大一部分仍然存在。这里提出的研究解决迫切需要阐明在PCA生物学中更具侵略性PCA生物学的分子机制 AA男子，操纵这些机制用于治疗应用，并确定这些机制反应当前治疗策略的机制。在Duke Cancer Institute（DCI），我们已经确定了AA与白色的新型剪接基因 PCA并表明AA变体轨迹具有更具侵略性的癌症侵袭特征AA中的PCA 男人。我们还确定了位于剪接调节区域中的新型单核苷酸多态性与PCA风险，侵略性和生存相关的基因。这些基因的子集是雄激素受体（AR）靶标，鉴于AR信号在PCA进展中的作用，使用抗雄激素的作用 AR信号与PCA健康差异的治疗和关联。并联，在北卡罗来纳州中央大学（NCCU），我们询问了AMP激活的蛋白激酶（AMPK）信号，该信号在A中运行具有AR的调节环，因此对与种族相关的PCA具有治疗意义。使用生物制造 NCCU的研究所和技术企业，我们确定了8个新型的小分子AMPK激活剂。拟议的工作是一个联合转化科学试点项目，旨在进一步开发现有的NCCU-DCI 合作伙伴关系，支持癌症研究中的集中合作，增强NCCU和癌症的癌症研究 DCI的健康差异研究并支持2个初级教师和少数族裔博士后的发展。我们的目标是1）询问和调节与种族相关的AR目标剪接变体和2）阐明遗传种族和种族之间和种族之间对抗雄激素治疗的反应很重要的因素。具体来说，我们的目标到1）定义调节与种族相关的AR目标RNA剪接变体水平的生物学意义 PCA细胞生物学，使用新型RNA疗法和小分子，2）定义顺式的生物学意义 AA PCA中剪接的AR靶基因的作用剪接元件与替代RNA剪接事件和与种族相关的PCA细胞生物学，通过表达包含AA或白色基因型的变体并评估剪接和PCA细胞生物学的改变以及3）定义与替代RNA剪接有关的生物学因素事件和AMPK信号对于响应抗雄激素，乙酸阿比罗酮的响应至关重要种族群体之间，在临床试验中对临床参数进行关联分析。这里提出的工作的基本原理和影响是，它将揭示分子机制可以为开发新颖的精密生物标志物的道路铺平道路，以实现PCA风险，侵略性，治疗性少数民族之间的反应和/或生存预测以及PCA差异的精确治疗。