Biological & Environmental Mediators of Vitamin D and Aggressive Prostate Cancer

生物

• 批准号: 8794426
• 负责人: Adam Bryant Murphy
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8794426
• 关键词: 25-hydroxyvitamin D; Affect; African American; Analysis of Covariance; Animal Model; Antineoplastic Agents; Apoptosis; Apoptotic; Appointment; Area; Award; Basal Cell; Basic Science; Benign; Biological; Biological Assay; Biological Markers; Cell Culture Techniques; Cell Proliferation; Chicago; Clinic; Clinical; Clinical Trials; Collaborations; Communities; Confidence Intervals; Consultations; DNA Nucleotidylexotransferase; Data; Data Analyses; Databases; Department of Defense; Dihydroxycholecalciferols; Disease; Dissection; Education; Environment; Epidemiologic Studies; Epithelial; Epithelial Cells; Epithelium; Equation; Formalin; Freezing; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Polymorphism; Genotype; Gleason Grade for Prostate Cancer; Grant; Health Care Costs; Human; Illinois; Immunohistochemistry; In Vitro; Incidence; Institution; Intervention; Knowledge; Label; Lasers; Lead; Link; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediator of activation protein; Medical center; Mentors; Mentorship; Metabolic Pathway; Metabolism; Methods; Mixed Function Oxygenases; Modeling; Newly Diagnosed; Normal Range; Outcome; PSA Velocity; Paraffin Embedding; Pathway interactions; Patients; Pattern; Phase; Physicians; Population; Property; Prostate; Prostate carcinoma; Prostatectomy; Prostatic; Prostatic Neoplasms; Protocols documentation; Proxy; RNA; Race; Radical Prostatectomy; Relative (related person); Research; Research Personnel; Research Training; Residencies; Reverse Transcription; Risk; Role; Sample Size; Scientist; Serum; Slide; Specimen; Specimen Handling; Staging; Staining method; Stains; Testing; Therapeutic; Therapeutic Uses; Time; Tissue Banking; Tissue Banks; Tissues; Training; Transferase; Universities; Urologist; Urology; Veterans; Visit; Vitamin D; Vitamin D Analog; Vitamin D Deficiency; Vitamin D3 Receptor; Vitamins; Width; abstracting; androgen independent prostate cancer; base; cancer cell; cancer education; career development; epidemiologic data; gene discovery; genetic epidemiology; health administration; high risk; in vitro testing; in vivo; insight; laser capture microdissection; meetings; men; mortality; outcome forecast; prevent; prostate cancer cell line; public health relevance; skills; tumor; tumor progression

DESCRIPTION (provided by applicant): Murphy, Adam B. Biological and Environmental Mediators of Vitamin D and Aggressive Prostate Cancer! Candidate: Dr. Adam Murphy is an academic urologist who completed residency two years ago. Adam aims to deepen his basic science skills to be a well-rounded translational scientist. He is in his final year of a mentored Department of Defense Physician Research Training Award focused on the role of vitamin D and related genetic polymorphisms in prostate cancer heath disparities. Dr. Kittles is the primary mentor on his DOD grant prepared Adam to lead related protocols and community-based projects. The career development provided by the proposed protocol would deepen his knowledge of immunohistochemistry, specimen processing, laser capture micro-dissection, tissue banking, genotyping and gene expression analysis. The current translational project focuses on validating serum and prostatic vitamin D as an anti-cancer agent with therapeutic potential in human prostate cancer tumors. The training plan includes Genetic Epidemiology and Clinical Trials will spur him to be an independent translational researcher. Environment: Adam has dual appointments at Jesse Brown VA Medical Center and Northwestern University in the Department of Urology. Also, Adam now has visiting researcher status at University of Illinois at Chicago. Dr. Andre K. Balla and Adam met over a year ago and have planned this protocol jointly with consultation from Dr. Kittles. Dr. Murphy has developed appropriate collaborations across 3 Chicago area institutions with the right researchers and a study coordinator. Dr. Murphy also developed a weekly Prostate Cancer Education Clinic for all men with newly diagnosed prostate cancer at Jesse Brown VA to provide education, to streamline the pathway to treatment and to facilitate research recruitment within the Jesse Brown Urology clinics. Research: Dr. Murphy's research protocols have been focused on database analysis, basic genetic data analysis and community based participatory projects. In order to be translational, Dr. Murphy will deepen his basic science skill set by training and mentorship provided by this project. Abstract: Vitamin D has anti-cancer properties in vitro in normal prostate epithelial cells, in prostate cancer cell lines, and in animal models. Activated vitamin D, 1,25 dihydroxyvitamin D, is known to reduce proliferation and promote apoptosis in prostate cancer cell lines. In several epidemiologic studies, vitamin D deficiency is associated with increased risk of prostate cancer and in some studies, aggressive disease. However serum vitamin D levels may not accurately reflect the vitamin D levels in the prostate as the normal prostate has the hydroxylases to activate and metabolize vitamin D. Prostate cancer cell lines have been shown to commonly lose 1-alpha hydroxylase activity with tumor progression. Therefore we seek to 1) validate serum vitamin D as a proxy for intra-prostatic vitamin D levels using the expressed prostatic secretion from 260 prostatectomy specimen; 2) estimate the effect of vitamin D on rates of proliferation and apoptosis in 240 prostate tumors by evaluating percentage of cancer cells undergoing proliferation and apoptosis as a function of vitamin D tertile using a Ki-67 and a direct TUNEL assay on formalin fixed paraffin embedded tissue; 3) evaluate for changes in relative gene expression in the vitamin D metabolic pathway with tumor progression in fifty low grade tumors (Gleason < 6) versus fifty high grade tumors (Gleason 8-10).

描述（由申请人提供）： 墨菲，亚当B。维生素D和侵袭性前列腺癌的生物和环境介质！候选人：亚当·墨菲博士是一位学术泌尿科医生，两年前完成了住院医师实习。亚当的目标是加深他的基本科学技能，成为一个全面的翻译科学家。他是在他的指导国防部医师研究培训奖的最后一年，重点是维生素D和相关的遗传多态性在前列腺癌健康差异的作用。基特尔斯博士是他的国防部赠款准备亚当领导相关的协议和社区为基础的项目的主要导师。拟议方案提供的职业发展将加深他对免疫组织化学、标本处理、激光捕获显微解剖、组织库、基因分型和基因表达分析的了解。目前的翻译项目的重点是验证血清和前列腺维生素D作为一种抗癌剂，在人类前列腺癌肿瘤中具有治疗潜力。培训计划包括遗传流行病学和临床试验将促使他成为一名独立的翻译研究人员。环境：亚当在杰西布朗退伍军人医疗中心和西北大学泌尿系有双重任命。此外，亚当现在是芝加哥伊利诺斯大学的访问研究员。Andre K.博士巴拉和亚当在一年多前见过面，并在基特尔斯博士的咨询下共同计划了这一方案。Murphy博士与合适的研究人员和研究协调员在3个芝加哥地区机构开展了适当的合作。Murphy博士还为弗吉尼亚州杰西布朗的所有新诊断前列腺癌的男性开设了每周一次的前列腺癌教育诊所，以提供教育，简化治疗途径，并促进杰西布朗泌尿科诊所内的研究招募。研究：Murphy博士的研究方案一直专注于数据库分析，基本遗传数据分析和基于社区的参与性项目。为了翻译，墨菲博士将通过该项目提供的培训和指导来加深他的基本科学技能。翻译后摘要：维生素D在体外正常前列腺上皮细胞，前列腺癌细胞系，和动物模型中具有抗癌特性。已知活化的维生素D，即1，25二羟维生素D，可减少前列腺癌细胞系的增殖并促进细胞凋亡。在一些流行病学研究中，维生素D缺乏与前列腺癌风险增加有关，在一些研究中，与侵袭性疾病有关。然而，血清维生素D水平可能不能准确反映前列腺中的维生素D水平，因为正常前列腺具有羟化酶来激活和代谢维生素D。前列腺癌细胞系已显示通常随着肿瘤进展而丧失1-α羟化酶活性。因此，我们寻求1）使用260例前列腺切除术标本的前列腺液来验证血清维生素D作为前列腺内维生素D水平的代表; 2）通过使用Ki-67评估经历增殖和凋亡的癌细胞百分比作为维生素D三分位数的函数，评估维生素D对240个前列腺肿瘤中增殖和凋亡速率的影响。67和在福尔马林固定的石蜡包埋的组织上的直接TUNEL测定; 3）在50个低级别肿瘤（Gleason < 6）与50个高级别肿瘤（Gleason 8-10）中评价维生素D代谢途径中的相对基因表达随肿瘤进展的变化。