Project 1: Disparities in Mitochondrial Peptidomics and Transcriptomics in Prostate Cancer

线粒体功能障碍和线粒体DNA多态与前列腺癌(PC)生物学相关。 我们发现了一类新的线粒体衍生多肽(MDP)，它是从小的开放转录而来的 线粒体DNA中的读框。这些药物包括正在流通的HERMIN、SHLP-2和MOTS-C。 细胞保护性信号肽。MDP水平降低与老年性疾病有关，我们 最近发现，黑人的血液中人红素和SHLP2水平低于白人。我们假设 少数族裔男性相对于白人的MDP表达差异是导致PC风险增加的原因之一。我们 寻求测试血浆MDP及其前列腺癌表达水平作为PC风险生物标志物的潜力，两者都 作为诊断前生物标志物和替代预后风险指标在一组患有和不患有PC的男性中的应用 包括白人、拉丁裔和黑人男性。我们最近报道，在一小群黑人和白人男性中 在接受前列腺活检时，前列腺癌患者的SHLP2水平显著低于非前列腺癌患者，而且 黑人男性的水平明显低于白人男性。SHLP2水平&gt；350pg/ml为阴性预测 无论种族，对于阴性的活检，≥的值为95%，并且可能是避免活检的一个很好的生物标志物。一个 需要更大的数据集来验证我们的结果，而这笔拨款将极大地扩展这一研究问题 看看其他的种族群体和他们的亚群。我们这个项目的第一个目标包括分析 研究少数民族人群血清SHLP2水平与PC风险的关系。我们将利用两个正在进行的 UF和USC的样本收集工作分析了700个白人、拉丁裔和黑人男性的血清样本(AIM 1)。SHLP2水平将在患有和不患有PC的男性之间进行比较，并按种族分层。我们的第二个目标是 确定不同种族男性中额外的血浆MDP与PC风险之间的关联。 我们将测定血浆中人蛋白、MOTS-c、SHLP2和SHLP6的水平，并确定它们之间的关系 在这些MDP之间，种族和癌症状况(目标2)。用全转录组RNAseq分析RNA 从来自黑人、白人和拉丁裔前列腺癌患者的显微解剖的FFPE中，我们将比较 前列腺癌MDP转录本的差异表达及其与肿瘤严重程度和预后的关系 民族血统(目标3)。最后，我们将检验线粒体DNA拷贝数在 前列腺癌的风险和严重性与血液循环和良性和恶性前列腺组织中的前列腺癌密切相关。我们的研究将是第一个 线粒体DNAcn，线粒体衍生肽表达和水平的种族差异的综合研究， 以及它们对PC的影响。如果成功，MDP水平可作为PC的诊断生物标志物，尤其是在 少数族裔男性。预期的发现是，MDP水平受到干预措施的调节，这些干预措施可能会改变癌症风险 (如饮食和锻炼，这会提高MDP水平)可能会导致一种简单的方法，即高危男性获得 检测水平，并建议改变生活方式，从一开始就不会患上这种疾病。

Mitochondrial dysfunction and mtDNA polymorphisms have been associated with prostate cancer (PC) biology. We discovered a novel class of mitochondria-derived peptides (MDPs) that are transcribed from small open reading frames within the mtDNA. These include humanin, SHLP-2, and MOTS-c, which are circulating cytoprotective signaling peptides. Decreased MDP levels have been implicated in diseases of aging, and we recently found that Blacks have lower circulating levels of humanin and SHLP2 than Whites. We hypothesize that differences in MDP expression in minority men relative to Whites contribute to the elevated risk of PC. We seek to test the potential of plasma MDPs and their prostate expression levels as biomarkers for PC risk, both as pre-diagnostic biomarkers and as surrogate prognostic risk indicators in a group of men with and without PC including White, Latino, and Black men. We recently reported that in a small cohort of Black and White men undergoing prostate biopsy SHLP2 levels were significantly lower in men with PC vs. men without PC and that Black men had significantly lower levels than White men. A SHLP2 level >350 pg/ml had a negative predictive value of ≥95% for a negative biopsy regardless of race and may be an excellent biomarker to avoid biopsy. A larger dataset is needed to validate our results, and this grant will dramatically expand this research question and look at additional ethnic groups and their subpopulations. Our first goal for this project includes the analysis of the association between serum SHLP2 levels and PC risk in ethnic minorities. We will leverage two ongoing sample collection efforts at UF and USC to analyze 700 serum samples from White, Latino, and Black men (Aim 1). SHLP2 levels will be compared between men with and without PC and stratified by race. Our second goal is to determine the association between additional plasma MDPs and PC risk among men of different ethnicities. We will measure plasma levels of humanin, MOTS-c, SHLP2, and SHLP6 and determine the association between these MDPs, race, and cancer status (Aim 2). Using whole transcriptome RNAseq analysis of RNA from micro-dissected FFPE from prostate tumor patients who are Black, White, and Latino we will compare the prostate mito-transcriptome for divergent expression of MDP transcripts and their relation to cancer severity and ethnic origin (Aim 3). Finally, we will examine the contribution of mitochondrial DNA copy number in the circulation and in benign and malignant prostate tissues, to PC risk and severity. Our study will be the first comprehensive study of racial differences in mtDNAcn, mitochondrial-derived peptide expression and levels, and their effect on PC. If successful, MDP levels may serve as diagnostic biomarkers of PC, particularly in minority men. The expected finding, that MDP levels are regulated by interventions that may modify cancer risk (such as diet and exercise, which raise MDP levels) could lead to a simple approach where at-risk men get their level measured and are counseled to make a lifestyle modification and never get the disease in the first place.