Inhibition of Prostate Carcinogenesis & Tumor Growth by Energy Restriction-Mimeti

抑制前列腺癌发生

基本信息

批准号：
8605945
负责人：
Lisa Danielle Berman-Booty
金额：
$ 13.23万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-04 至 2014-10-25
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8605945
关键词：
2,4-thiazolidinedione Ablation Adenocarcinoma Adverse effects American Anatomy Animal Model Animals Applications Grants Award Biochemical Biomedical Research Cancer Etiology Castration Cell Death Cells Cellular biology Cessation of life Chemoprevention Chemopreventive Agent Chronic Clinical Trials Collaborations Data Defect Deoxyglucose Development Development Plans Diet Discipline Disease Resistance Doctor of Philosophy Energy Metabolism Enrollment Environment Epigenetic Process Epithelial Cells Exhibits Faculty Funding Future Genetic Glucose Glycolysis Goals Growth Heterogeneity Hormonal Human In Vitro Incidence Inhibitory Concentration 50 Institution Interdisciplinary Study K-Series Research Career Programs Knock-out Knowledge LNCaP Laboratories Licensing Malignant Neoplasms Malignant neoplasm of prostate Manuscripts Mediating Medical Castration Mentors Mentorship Metabolic Metabolism Modeling Molecular Molecular Biology Mus Non-Malignant Nude Mice Ohio Oral PC3 cell line PTEN gene Pathology Peroxisome Proliferator-Activated Receptors Pharmaceutical Chemistry Pharmacology Pharmacy facility Phase Positioning Attribute Postdoctoral Fellow Pre-Clinical Model Prevention strategy Principal Investigator Prostate Prostatic Prostatic Neoplasms Recurrence Research Research Training Residencies Resources Resveratrol Safety Schools Scientist Signal Transduction Starvation Techniques Testing Therapeutic Thiazolidinediones Time Toxic effect Training Training Programs Transgenic Mice Transgenic Organisms Universities Urogenital Cancer Validation Veterinarians Warburg Effect Western Blotting Writing Xenograft Model Xenograft procedure aerobic glycolysis anticancer research base cancer cell cancer chemoprevention cancer prevention cancer therapy carcinogenesis career career development ciglitazone college cytotoxicity deprivation design endoplasmic reticulum stress experience gene induction glucose uptake graduate student human cancer mouse model human disease improved in vivo member men mimetics mouse model neoplastic cell novel pre-clinical professor prostate cancer cell prostate cancer prevention prostate carcinogenesis response scaffold skills small molecule tool tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): The Candidate: Dr. Lisa Berman-Booty is a licensed veterinarian currently enrolled in the combined anatomic pathology residency and graduate research-training program in the Department of Veterinary Biosciences at The Ohio State University. The funding provided by the K01 SERCA would support Dr. Berman-Booty for the next five years of her career, which will include her final two years of graduate school (culminating with the completion of her Ph.D.) and her first three-years as an independent principal investigator. The Environment: Dr. Berman-Booty's training will be coordinated through the Department of Veterinary Biosciences, a multidisciplinary research environment that combines multiple research disciplines into a cohesive academic unit. The resources, guidance, and collaborations provided by the faculty members in the department will enable Dr. Berman-Booty to develop into a successful independent scientist. Dr. Berman- Booty's primary mentor, Dr. Ching-Shih Chen, is a Professor of Medicinal Chemistry at The Ohio State University College of Pharmacy. Dr. Chen is an expert in the field of medicinal chemistry and the development of novel chemotherapeutics. He has mentored many graduate students and postdoctoral fellows. Dr. Thomas Rosol and Dr. Steven Clinton, members of Dr. Berman-Booty's mentorship committee, have expertise in the study of urogenital cancer, prostate pathology, chemoprevention, and mouse models of human cancer. The Training and Career Development Plans: Training and career development during this award period will include the mastery of new techniques in molecular biology, study of the newest developments in the field of cancer research, and further refinement of grantsmanship and manuscript writing skills. The primary mentor and the mentorship committee will closely supervise the training. The five-year training plan consists of two phases. K award funding during phase I (years 1 and 2) will allow Dr. Berman-Booty to devote approximately 90% of her time to research and include the completion of her Ph.D. K award funding during phase II (years 3, 4, and 5) will allow Dr. Berman-Booty to transition to a position as a junior faculty member. Career Goals: Dr. Berman-Booty's immediate career goals include completing the research for her dissertation and becoming an independent research scientist and junior faculty member at the Ohio State University. Her long-term career goals are to obtain a tenure track position at an academic institution, develop additional animal models of human cancer, and continue her research into cancer prevention and treatment. The Proposal: A hallmark of cancer cells is a shift in cellular energy metabolism to aerobic glycolysis (the Warburg effect). This is associated with increased glycolytic flux and energy metabolism. While this metabolic shift provides growth advantages to cancer cells, it also presents opportunities to exploit the peculiarities of tumor cell metabolism for therapeutic and/or chemopreventive purposes. Dietary energy restriction has been effective in suppressing carcinogenesis in various animal models. Additionally, recent research has demonstrated the in vitro and in vivo antitumor efficacies of the energy restriction mimetic agents (ERMAs) 2- deoxyglucose (2-DG) and resveratrol. However, the utilization of energy restriction as a means of human cancer prevention and treatment is untenable, and the anti-tumor potencies of 2-DG and resveratrol are relatively low. We have recently developed two novel ERMAs, derived from the thiazolidinedione ciglitazone, that exhibit higher in vitro potency than 2-DG and resveratrol. The focus of this grant application is to evaluate the effects of these ERMAs (CG12 and CG5) in preclinical models of prostate cancer. The central hypothesis to be tested is that the unique abilities of CG12 and CG5 to target energy metabolism have translational potential in prostate cancer prevention. To test this hypothesis, we will utilize human prostate cancer cell lines, xenograft mouse models, and transgenic mice that autochthonously develop prostate cancer.

描述（由申请人提供）：候选人：Lisa Berman-Booty 博士是一名执业兽医，目前在俄亥俄州立大学兽医生物科学系参加解剖病理学住院医师培训和研究生研究培训相结合的项目。 K01 SERCA 提供的资金将支持 Berman-Booty 博士未来五年的职业生涯，其中包括她研究生院的最后两年（最终完成博士学位）和她的前三年 -担任独立首席研究员多年。环境：Berman-Booty 博士的培训将通过兽医生物科学系进行协调，该系是一个多学科研究环境，将多个研究学科结合成一个有凝聚力的学术单位。该系教员提供的资源、指导和合作将使伯曼-布蒂博士发展成为一名成功的独立科学家。 Berman- Booty 博士的主要导师 Ching-Shih Chen 博士是俄亥俄州立大学药学院的药物化学教授。陈博士是药物化学和新型化疗药物开发领域的专家。他指导过多名研究生和博士后。 Berman-Booty 博士导师委员会成员 Thomas Rosol 博士和 Steven Clinton 博士在泌尿生殖癌、前列腺病理学、化学预防和人类癌症小鼠模型研究方面拥有专业知识。培训和职业发展计划：本奖项期间的培训和职业发展将包括分子生物学新技术的掌握、癌症研究领域最新进展的研究以及资助技巧和稿件写作技巧的进一步完善。首席导师和导师委员会将密切监督培训。五年培训计划分为两个阶段。第一阶段（第一年和第二年）的 K 奖资金将使 Berman-Booty 博士能够将大约 90% 的时间用于研究，包括完成博士学位。第二阶段（第 3 年、第 4 年和第 5 年）的 K 奖资金将使 Berman-Booty 博士能够过渡到初级教员的职位。职业目标：Berman-Booty 博士的近期职业目标包括完成论文研究并成为俄亥俄州立大学的独立研究科学家和初级教员。她的长期职业目标是在学术机构获得终身职位，开发更多的人类癌症动物模型，并继续她对癌症预防和治疗的研究。提案：癌细胞的一个标志是细胞能量代谢向有氧糖酵解的转变（瓦尔堡效应）。这与糖酵解通量和能量代谢的增加有关。虽然这种代谢转变为癌细胞提供了生长优势，但它也提供了利用肿瘤细胞代谢特性用于治疗和/或化学预防目的的机会。在各种动物模型中，饮食能量限制可有效抑制致癌作用。此外，最近的研究证明了能量限制模拟剂 (ERMA)、2-脱氧葡萄糖 (2-DG) 和白藜芦醇的体外和体内抗肿瘤功效。然而，利用能量限制作为人类癌症预防和治疗的手段是站不住脚的，并且2-DG和白藜芦醇的抗肿瘤效力相对较低。我们最近开发了两种新型 ERMA，源自噻唑烷二酮环格列酮，其体外效力高于 2-DG 和白藜芦醇。本次拨款申请的重点是评估这些 ERMA（CG12 和 CG5）在前列腺癌临床前模型中的效果。要测试的中心假设是 CG12 和 CG5 靶向能量代谢的独特能力在前列腺癌预防中具有转化潜力。为了检验这一假设，我们将利用人类前列腺癌细胞系、异种移植小鼠模型和自发产生前列腺癌的转基因小鼠。