Pilot Project 1

非裔美国人(AA)前列腺癌(PCA)的发病率和死亡率高于 白色的。尽管许多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。在这里提出的研究 解决迫切需要阐明更具侵袭性的PCA生物学背后的分子机制 操纵这些机制用于治疗应用，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)，我们在再生障碍性贫血和白色再生障碍性贫血中发现了新的选择性剪接基因 并已表明AA变异与AA中的PCA具有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节区的新的单核苷酸多态。 这些基因与前列腺癌的风险、侵袭性和存活率有关。这些基因的亚群是雄激素。 受体(AR)靶点，考虑到AR信号在前列腺癌进展中所起的作用，使用抗雄激素 AR信号的治疗及其与前列腺癌健康差异的关联。同时，在北卡罗来纳州中央 ，我们已经询问了AMP激活的蛋白激酶(AMPK)信号，它在一种 AR的调节环路，因此对种族相关的PCa具有治疗意义。使用生物制造 NCCU的研究所和科技企业，我们确定了8个新的小分子AMPK激动剂。 拟议的工作是一项联合翻译科学试点项目，以进一步发展现有的NCCU-DCI 伙伴关系，支持癌症研究领域的重点合作，加强NCCU和癌症的癌症研究 在疾病控制与预防中心进行健康差距研究，并支持培养2名初级教员和一名少数族裔博士后。我们的 目标是1)询问和调节种族相关的AR靶剪接变异体和2)阐明遗传 种族间和种族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)确定调节种族相关AR靶RNA剪接变异体水平的生物学意义 Pca细胞生物学，使用新的RNA疗法和小分子，2)定义顺式-2)的生物学意义 AA-PCA中AR靶基因选择性剪接元件对选择性RNA剪接事件的作用 和AA种族相关的PCa细胞生物学，通过表达包含AA或白人基因型的变体并评估 剪接和前列腺癌细胞生物学的改变以及3)确定与RNA选择性剪接相关的生物学因素 事件和AMPK信号转导对于抗雄激素的反应至关重要。 在种族群体之间，进行与临床试验中临床参数的相关性分析。 这里提出的工作的基本原理和影响是，它将揭示 可以为开发新的用于PCa风险、侵袭性、治疗性的精密生物标记物铺平道路 少数族裔的反应和/或生存预测以及对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.