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)： 维生素D和侵袭性前列腺癌的生物和环境介体！候选人：亚当·墨菲博士是一位学术上的泌尿科医生，两年前完成了住院医师资格。亚当的目标是深化他的基本科学技能，成为一名全面发展的翻译科学家。他正在参加国防部医生研究培训奖的最后一年，该奖项的重点是维生素D和相关基因多态在前列腺癌健康差异中的作用。基特尔斯博士是他的国防部拨款的主要导师，让亚当准备领导相关的协议和基于社区的项目。拟议方案提供的职业发展将加深他在免疫组织化学、标本处理、激光捕获显微解剖、组织银行、基因分型和基因表达分析方面的知识。目前的翻译项目重点是验证血清和前列腺癌维生素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，这将促使他成为一名独立的翻译研究员。环境：亚当在退伍军人事务部杰西·布朗医学中心和西北大学泌尿外科兼职。此外，亚当现在芝加哥伊利诺伊大学拥有客座研究员的身份。安德烈·K·巴拉博士和亚当在一年多前相识，并在基特尔斯博士的咨询下共同规划了这一方案。墨菲博士已经在芝加哥地区的3个机构与合适的研究人员和研究协调员开展了适当的合作。墨菲博士还在弗吉尼亚州杰西布朗为所有新诊断为前列腺癌的男性设立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诊所内的研究招募。研究：墨菲博士的研究方案侧重于数据库分析、基本遗传数据分析和基于社区的参与性项目。为了成为翻译，墨菲博士将通过这个项目提供的培训和指导来加深他的基本科学技能。摘要：维生素D在正常前列腺上皮细胞、前列腺癌细胞系和动物模型中具有体外抗癌作用。活性维生素D，1，25-二羟基维生素D，已知可抑制前列腺癌细胞系的增殖并促进其凋亡。在几项流行病学研究中，维生素D缺乏与前列腺癌风险增加有关，在一些研究中还与侵袭性疾病有关。然而，血清维生素D水平可能不能准确地反映前列腺中的维生素D水平，因为正常的前列腺具有激活和代谢维生素D的羟基酶。已有研究表明，随着肿瘤的进展，前列腺癌细胞株通常失去1-α羟基酶的活性。因此，我们寻求1)使用260例前列腺切除标本中表达的前列腺分泌物来验证血清维生素D是否可作为前列腺癌内维生素D水平的指标；2)通过使用Ki-67和对福尔马林固定的石蜡包埋组织进行直接TUNEL检测来评估240例前列腺癌(Gleason；6)和50例高级别肿瘤(Gleason 8-10)中维生素D对癌细胞增殖和凋亡的影响；3)评估50例低级别肿瘤(Gleason&lt；6)和50例高级别肿瘤(Gleason 8-10)中维生素D代谢途径中相关基因表达的变化。