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

• 批准号: 8507659
• 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
• 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/8507659
• 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

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，旨在将首席研究员培养为独立的转化研究员，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的理解，数据解释，动物建模和实验设计。还将在资助和科学写作方面进行额外的指导。弗兰克·托蒂博士将是主要导师。他是一位著名的临床医生和资金雄厚的研究人员，也是维克森林大学癌症生物学系主任和综合癌症中心主任。他成功地将许多学生和博士后培养成独立的研究人员。他的指导将与一组资深教员一起进行。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具有丰富的临床和研究经验。该研究计划将探讨脂肪酸合成酶（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。急性髓细胞和淋巴细胞白血病是侵袭性恶性肿瘤，其特点是对治疗有耐药性，成人预后差。线粒体代谢的改变与白血病细胞的耐药性有关。具体目的是：1)确定PDH和FASN抑制对白血病细胞活力和线粒体代谢的体外和体内影响。2)确定PDH和FASN抑制对急性白血病细胞体内外标准治疗和靶向治疗反应的影响。3)测定体外外源脂肪酸和体内日粮脂肪酸对其的影响