Pilot Project 1

非裔美国人（AAs）的前列腺癌（PCa）发病率和死亡率高于 白人虽然大部分不同的癌症负担可以用不同的社会决定因素来解释， 在健康方面，在控制了这些因素之后，这种差距的很大一部分仍然存在。这里提出的研究 解决迫切需要阐明的分子机制，更积极的PCa生物学， AA男性，操纵这些机制的治疗应用，并确定这些机制的重要性， 对当前治疗策略的反应机制。 在杜克癌症研究所（DCI），我们已经确定了新的选择性剪接基因在AA与白色 PCa和已经显示AA变体跟踪AA中PCa的更具侵袭性的癌症侵袭特征， 男人我们还发现了位于剪接调控区的新的单核苷酸多态性， 这些基因与前列腺癌的风险，侵略性和生存有关。这些基因的子集是雄激素 受体（AR）靶点，考虑到AR信号传导在PCa进展中的作用，使用抗雄激素 治疗和AR信号传导与PCa健康差异的关联。同时，在北卡罗来纳州中部 在NCCU的研究中，我们研究了AMP激活的蛋白激酶（AMPK）信号传导，它在一个 调节环与AR，因此具有种族相关的PCa的治疗意义。使用生物制造 在国立交通大学的研究所和科技企业，我们鉴定了8种新的小分子AMPK激活剂。 拟议的工作是一个联合转化科学试点项目，以进一步发展现有的NCCU-DCI 合作伙伴关系，支持癌症研究的重点合作，加强NCCU的癌症研究和癌症 在DCI的健康差距研究，并支持2初级教师和少数博士后的发展。我们 目的是1）询问和调节种族相关的AR靶向剪接变体，和2）阐明遗传学上的 种族群体之间对抗雄激素治疗反应的重要因素。具体来说，我们的目标是 1）定义调节种族相关AR靶RNA剪接变体水平的生物学意义， PCa细胞生物学，使用新的RNA治疗剂和小分子，2）定义顺式- AA PCa中可变剪接AR靶基因的剪接元件对可变RNA剪接事件的作用 和AA种族相关的PCa细胞生物学，通过表达含有AA或白色基因型的变体并评估 改变剪接和PCa细胞生物学和3）定义与选择性RNA剪接相关的生物学因素 事件和AMPK信号传导，对于对抗雄激素醋酸阿比特龙的反应至关重要， 在种族群体之间，在临床试验中进行相关因素与临床参数的关联分析。 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PCa风险、侵袭性、治疗性和生物学特性的新的精确生物标志物的开发铺平道路。 少数群体的反应和/或生存预测以及PCa差异的精确治疗。

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.