Metabolic contribution to cell viability and therapy resistance in the acute

急性疾病中代谢对细胞活力和治疗耐药性的贡献

基本信息

批准号：
8685202
负责人：
Timothy Sebastian Pardee
金额：
$ 16.8万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
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：
2012-07-09 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8685202
关键词：
Acetyl Coenzyme A Acute Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Acute leukemia Adult Aerobic Affect Age American Animal Cancer Model Animal Model Apoptosis BAY 54-9085 Bone Marrow Breast Cancer Cell Cancer Biology Cell Line Cell Survival Cell Therapy Cells Cessation of life Chairperson Citrates Citric Acid Cycle Clinical Research Comorbidity Comprehensive Cancer Center Comprehensive Cancer Center of Wake Forest University Core Facility Cytosol DNA Damage Data Development Diagnosis Diet Dietary Fats Dietary Fatty Acid Disease Disease Resistance Doxorubicin Drug Efflux Elderly Environment Enzymes Experimental Designs Faculty Fatty Acids Fatty-acid synthase Funding Goals HL60 Hematology Human In Vitro Knowledge Lead Leukemic Cell Leukocytes Lymphoblastic Leukemia Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Membrane Potentials Mentors Mentorship Metabolic Metabolism Methods Mitochondria Modeling Mus Outcome Oxidative Phosphorylation Palmitates Pathway interactions Patients Play Postdoctoral Fellow Principal Investigator Pyruvate Pyruvate Dehydrogenase Complex Radiation Research Research Personnel Research Project Grants Resistance Respiration Role Solid Neoplasm Source Students Testing Therapeutic Toxic effect Training Training Programs Tyrosine Kinase Inhibitor Universities Warburg Effect Work Writing anaerobic glycolysis bcr-abl Fusion Proteins cancer cell chemotherapy cytotoxic design experience fatty acid oxidation forest in vivo indexing insight leukemia lipoate malignant breast neoplasm member mitochondrial membrane model design mortality neoplastic cell novel novel strategies older patient oncology orlistat outcome forecast programs research study response synergism therapy resistant treatment strategy tumor metabolism

项目摘要

DESCRIPTION (provided by applicant): This proposal outlines a 5 year program designed to develop the principal investigator into an independent translational researcher and investigate the role of altered metabolism in leukemia cell viability and therapy resistance. The principal investigator is a junior faculty member at Wake Forest University. The mentoring and training program will focus on development of a deeper understanding of metabolism in cancer, data interpretation, animal modeling and experimental design. Additional mentoring in grantsmanship and scientific writing will also be undertaken. Dr Frank Torti will be the primary mentor. He is a renowned clinician and well funded researcher as well as the chairman of the department of Cancer Biology and director of the Wake Forest University Comprehensive Cancer Center. He has successfully developed many students and post-doctoral candidates into independent researchers. His mentorship will be in conjunction with a group of senior faculty members. Drs Kridel, Powell, Almeida-Porada and High will comprise the faculty mentoring committee. These investigators have a wealth of clinical and research experience in acute leukemias, cancer metabolism and animal models of cancer. The research plan will explore the contribution of fatty acid synthase (FASN) and pyruvate dehydrogenase complex (PDH) to cell viability and resistance to therapy in the acute leukemias. Acute myeloid and lymphocytic leukemias are aggressive malignancies characterized by resistance to therapy and poor outcomes in adults. Altered mitochondrial metabolism is associated with resistance in leukemia cells. The specific aims will: 1) Determine the effect of PDH and FASN inhibition on leukemia cell viability and mitochondrial metabolism in vitro and in vivo. 2) Determine the effects of PDH and FASN inhibition on response to standard and targeted therapy in acute leukemia cells in vitro and in vivo. 3) Determine the effects of exogenous fatty acids in vitro and dietary fatty acids in vivo on therapy response in the acute leukemias. Completion of these studies will provide novel insights on therapy response and lead to novel treatment strategies for patients who suffer from these aggressive malignancies. The Section on Hematology and Oncology, Department of Cancer Biology and the NCI designated Comprehensive Cancer Center at Wake Forest University will provide a rich environment, core facilities and expertise necessary for the successful completion of the proposed experiments. It is an ideal place to complete training towards becoming an independent translational researcher.

描述（由申请人提供）：该提案概述了一个为期 5 年的计划，旨在将主要研究者培养为独立的转化研究人员，并研究代谢改变在白血病细胞活力和治疗耐药性中的作用。首席研究员是维克森林大学的一名初级教员。指导和培训计划将侧重于加深对癌症代谢、数据解释、动物建模和实验设计的理解。还将进行资助和科学写作方面的额外指导。 Frank Torti 博士将担任主要导师。他是一位著名的临床医生和资金雄厚的研究员，也是癌症生物学系主任和维克森林大学综合癌症中心主任。他成功地将许多学生和博士后候选人培养成独立研究人员。他的指导将与一组高级教员一起进行。 Kridel 博士、Powell 博士、Almeida-Porada 博士和 High 博士将组成教师指导委员会。这些研究人员在急性白血病、癌症代谢和癌症动物模型方面拥有丰富的临床和研究经验。该研究计划将探讨脂肪酸合酶（FASN）和丙酮酸脱氢酶复合物（PDH）对急性白血病细胞活力和治疗耐药性的贡献。急性髓系白血病和淋巴细胞白血病是一种侵袭性恶性肿瘤，其特征是成人对治疗产生耐药性且预后不良。线粒体代谢的改变与白血病细胞的耐药性有关。具体目标是： 1) 确定 PDH 和 FASN 抑制对体外和体内白血病细胞活力和线粒体代谢的影响。 2) 确定 PDH 和 FASN 抑制对体外和体内急性白血病细胞标准和靶向治疗反应的影响。 3) 确定体外外源脂肪酸和体内膳食脂肪酸对急性白血病的治疗反应。这些研究的完成将为治疗反应提供新的见解，并为患有这些侵袭性恶性肿瘤的患者带来新的治疗策略。维克森林大学的血液学和肿瘤学科、癌症生物学系和 NCI 指定的综合癌症中心将为成功完成拟议实验提供丰富的环境、核心设施和专业知识。它是完成成为独立转化研究员培训的理想场所。