Metabolic Substrate Utilization During c-Myc Induced Cardiac Hypertrophy

c-Myc 诱导的心脏肥大过程中代谢底物的利用

• 批准号: 8486476
• 负责人: Aaron K Olson
• 金额: $ 12.9万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8486476
• 关键词: Adult; Advisory Committees; Apoptosis; Attenuated; Basic Science; Biochemical Pathway; Carbohydrates; Cardiac; Cardiac Myocytes; Cardiology; Cardiovascular system; Cell Cycle Proteins; Cell division; Cessation of life; Child; Childhood; Clinical; Communities; Development; Evaluation; Financial compensation; Genes; Genome; Goals; Heart Hypertrophy; Heart failure; Hypertrophy; Institution; Instruction; Investigation; Knowledge; Laboratories; Link; Literature; MYC Family Genes; Maintenance; Mediating; Mediator of activation protein; Mentors; Mentorship; Metabolic; Metabolism; Mus; Myocardial; Natural regeneration; Outcome; Patients; Pediatric Hospitals; Physicians; Play; Principal Investigator; Process; Protein Biosynthesis; Proto-Oncogenes; Research; Research Personnel; Resources; Role; Scientist; Signal Transduction; Stimulus; Stress; Technical Expertise; Testing; Training; Training Programs; Universities; Washington; abstracting; base; c-myc Genes; c-myc Proto-Oncogenes; carbohydrate metabolism; career; cell growth; cell growth regulation; disability; heart metabolism; improved; mortality; novel; oncology; pressure; research and development; response; skills; symposium

DESCRIPTION (provided by applicant): The primary goal described in this 5 year training program is the development of a career in academic Pediatric Cardiology. The principal investigator has completed clinical training w/ith two additional years focused on laboratory- based research. This proposal will extend the principal investigator's scientific skills through investigation into the role of metabolic substrate utilization changes in the development and maintenance of compensated cardiac hypertrophy. This plan includes the sponsor, Dr. Michael Portman, an expert on cardiac metabolism. Dr. David Hockenbery, co- mentor and consultant, will assist the project with his extensive knowledge on bioenergenic regulation of cell growth and division. Co-mentor Dr. Charles Murry (LJW) is an expert on cardiomyocyte development and regeneration will provide mentorship in evaluation of hypertrophy. A training plan is presenting including specific coursework, conferences and the formation of an Advisory Committee lo guide his development into a successful independent investigator. C-Myc (Myc) regulates hypertrophy and maintains cardiac function. However, the mechanisms are mostly unknown. The oncology literature identifies specific Myc gene networks including carbohydrate metabolism. Due to known links between metabolism and hypertrophy, we will investigate the metabolic network. We hypothesize that: Myc signals a metabolic shift towards carbohydrate utilization and that this shift mediates the development and maintenance of compensated hypertrophy. Our aims include: 1) Determine if a metabolic shift towards increased carbohydrate utilization temporally precedes the development of hypertrophy in Myc-induced mice, 2)Determine if inhibiting the Myc- induced substrate shift impairs the development and/or maintenance of compensated hypertrophy in these mice, 3)Determine whether Myc is a major mediator of increased myocardial carbohydrate metabolism in the response to pressure overload, 4) Determine if Myc induction in long-term aortic banded mice can preserve compensated hypertrophy through changes in cardiac substrate utilization. Children's Hospital has a strong commitment to basic science research and the development of physician-scientists. The University of Washington has a vibrant cardiovascular research community which can provide technical expertise as needed. The combined resources of these institutions will provide ample opportunity for the principal investigator to successfully develop into an academic pediatric cardiologist. RELEVANCE (See instructions): Heart failure has an annual mortality rate of around 10% in adults, therefore, researchers are constantly trying to identify new therapies to improve patient outcomes. The protooncogene Myc regulates compensated hypertrophy. A mechanistic understanding of the beneficial aspects of Myc-induced hypertrophy offers the potential for developing novel therapies for heart failure in adults and children. (End of Abstract)

描述（由申请人提供）：在这个5年的培训计划中描述的主要目标是在学术儿科心脏病学的职业发展。主要研究者已经完成了为期两年的临床培训，重点是实验室研究。该提案将通过研究代谢底物利用变化在代偿性心脏肥大的发展和维持中的作用来扩展主要研究者的科学技能。该计划包括赞助商，迈克尔波特曼博士，心脏代谢专家。大卫霍肯伯里博士，共同导师和顾问，将协助该项目与他的广泛知识，生物能源调节细胞生长和分裂。共同导师Charles Murry博士（LJW）是心肌细胞发育和再生方面的专家，他将在评估肥大方面提供指导。正在提出一项培训计划，包括具体的课程、会议和成立一个咨询委员会，以指导他成为一名成功的独立调查员。C-Myc（Myc）调节肥大并维持心脏功能。然而，其机制大多未知。肿瘤学文献鉴定了特定的Myc基因网络，包括碳水化合物代谢。由于已知代谢和肥大之间的联系，我们将研究代谢网络。我们假设：Myc标志着代谢向碳水化合物利用的转变，这种转变介导了代偿性肥大的发展和维持。我们的目标包括：1）确定朝向增加的碳水化合物利用的代谢转变是否暂时先于Myc诱导的小鼠中肥大的发展，2）确定抑制Myc诱导的底物转变是否损害这些小鼠中代偿性肥大的发展和/或维持，3）确定Myc是否是响应于压力超负荷的心肌碳水化合物代谢增加的主要介体，4）确定在长期主动脉结扎小鼠中Myc诱导是否可以通过心脏底物利用的变化来保持代偿性肥大。儿童医院对基础科学研究和医生科学家的发展有着坚定的承诺。华盛顿大学有一个充满活力的心血管研究社区，可以根据需要提供技术专长。这些机构的综合资源将为主要研究者成功发展成为学术儿科心脏病专家提供充足的机会。相关性（参见说明）：心力衰竭在成年人中的年死亡率约为10%，因此，研究人员一直在努力寻找新的治疗方法来改善患者的预后。原癌基因Myc调节代偿性肥大。对Myc诱导的肥大的有益方面的机制理解为开发成人和儿童心力衰竭的新疗法提供了可能。 (End摘要）