Mechanisms of Reduced Fatty Acid Oxidation and Cardiac Dysfunction in Sepsis

脓毒症中脂肪酸氧化减少和心脏功能障碍的机制

• 批准号: 8278334
• 负责人: Konstantinos Drosatos
• 金额: $ 13.38万
• 依托单位: COLUMBIA 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: 2012-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278334
• 关键词: Acquaintances; Address; Adenoviruses; Advisory Committees; Affect; Agonist; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Area; Award; Bacterial Infections; Binding; Bioinformatics; Biology; Biomedical Research; C57BL/6 Mouse; CD14 gene; Cardiac; Cardiac Myocytes; Cardiology; Cardiovascular system; Caring; Cause of Death; Cells; Chemicals; Chronic; Computer Simulation; DNA; Data; Development; Disease; Down-Regulation; Echocardiography; Education; Energy Metabolism; Environment; Experimental Designs; Family; Fatty Acids; Foundations; Functional disorder; Funding; Gene Expression; Generations; Genes; Glucose; Goals; Grant; Heart; Heart failure; Hypotension; In Vitro; Inflammation; Institutes; Intensive Care Units; Intervention; Ischemia; JNK-activating protein kinase; JUN gene; Knockout Mice; Knowledge; Laboratories; Lead; Link; Lipopolysaccharides; MAPK8 gene; Mediating; Medicine; Mentors; Meta-Analysis; Methods; Modeling; Molecular; Multiple Organ Failure; Mus; N-terminal; Nuclear Receptors; Organ; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Phase; Positioning Attribute; Precipitation; Principal Investigator; Production; Proteins; Recombinants; Research; Research Technics; Resistance; Role; Scientist; Sepsis; Septic Shock; Signal Pathway; Signal Transduction; Small Interfering RNA; Stress; Techniques; Technology; Testing; Therapeutic; Training; Universities; Work; Writing; base; biomedical informatics; career; chromatin immunoprecipitation; cost; design; effective therapy; falls; fatty acid metabolism; fatty acid oxidation; heart cell; heart function; high throughput analysis; improved; in vivo; member; mortality; new technology; notch protein; novel; novel strategies; novel therapeutics; oxidation; pressure; prevent; promoter; research study; responsible research conduct; rosiglitazone; septic; skills; successful intervention; toll-like receptor 4; tool; transcription factor

DESCRIPTION (provided by applicant): The proposed research study will facilitate the improvement of the education and career goals of the principal investigator (PI). Moreover, the PI will investigate the mechanisms that underlie reduced cardiac fatty acid oxidation during sepsis. The PI has set up an educative plan for the first two years (K99 phase) of the proposed study. This plan includes courses about bioinformatics tools, grant writing and responsible conduct of research. In addition, the PI will be trained in research techniques by his mentor and other experts, who are members of his advisory committee. The PI will perform experiments to investigate mechanisms that can increase cardiac fatty acid oxidation and will suggest therapeutic approaches for the treatment of cardiac septic shock. Upon conclusion of the mentored phase the PI will have established a pool of data, knowledge and new skills that will enhance his credentials for successful transition to independence. During the K99 phase the PI has planned to attend one course on Biomedical Informatics, one on grant writing and another in the responsible conduct of research. In addition, he has set up a training plan with his mentor and his advisors/collaborators that will provide him with technical knowledge on how to perform echocardiography, induction of heart failure in animal models, chromatin immunoprecipitation and high throughput analysis tools and methods. These techniques represent useful tools that he will be able to transfer to his own lab. Besides the new techniques that he will acquire, the proposed project requires knowledge in areas that he has only recently been associated with, such as inflammation and Kr¿ppel-like factor biology. Therefore, he has included in his advisory board a number of scientists with outstanding careers in these particular fields that will provide guidance of the highest possible level. All his advisors are employed by top- notch academic departments. They have agreed to invite the PI to present his work within their institutes, so that he receives input by a broad scientific audience and expands his scientific network. This will promote his transition to an independent research position and provide him a robust scientific foundation from which to apply for R01-level funding. The proposal core questions are: (1) Can stimulation of energy production prevent LPS-mediated cardiac dysfunction? (2) How does LPS lead to changes in cardiac energetics? (3) How can the reduction in FAO be prevented in LPS treated animals? To address these questions the PI has designed an experimental plan with two branches. The first falls into the K99 phase and is based on preliminary data of the current submission. This set of experiments aims to identify the mechanism that makes PPAR? a more potent activator of fatty acid oxidation when PPAR¿ is downregulated, like it happens in sepsis. Also, the PI will investigate the role of the JNK signaling pathway, which is activated by sepsis, in the reduction of the expression of PPAR¿, a protein that has been strongly associated with fatty acid oxidation. Furthermore, a new animal model with cardiomyocyte specific deletion of KLF5 will be generated and tested for resistance to cardiac dysfunction during sepsis. Besides, this novel animal model will be characterized with high throughput analysis methods and new targets may come up. The second branch of his plan falls into the R00 phase. Certain interventions that have been used successfully in the preliminary results and prevent sepsis will be explored for their therapeutic potential in heart failure. The elucidation of the mechanisms that will be investigated in the K99 phase will also identify new targets and may suggest novel approaches for the treatment of sepsis. Application of these successful interventions, as well as targeting of new factors that the high throughput analysis is going to indicate will be used to prevent sepsis-mediated cardiac dysfunction, as well as to treat other conditions of cardiac dysfunction with impaired fatty acid oxidation, such as pressure overload heart failure. Therefore, after his training in new technologies and generation of heart failure models, his transition to independent position will be facilitated due to his increased capacity to apply methods that prevent sepsis-associated cardiac dysfunction and pressure overload heart failure, aiming to provide novel treatments for these diseases. Overall, the current proposal will equip the PI with novel knowledge and useful tools to continue for independent career in molecular cardiology and stress signaling. His training plan has been designed to facilitate flawless production of data in the prominent environment of the Department of Medicine of the Columbia University, as well as the PI's acquaintance with modern tools of biomedical research that he will transfer to his independent laboratory. Approval of his application for the K99R00 award will result in the precise definition of novel mechanisms, which affect cardiac fatty acid oxidation and will thereby provide potential new therapeutics for the treatment of septic shock and heart failure.

描述（由申请人提供）：拟议的研究将促进主要研究者（PI）的教育和职业目标的改善。此外，PI 将研究败血症期间心脏脂肪酸氧化减少的机制。为拟议研究的前两年（K99 阶段）制定教育计划。该计划包括有关生物信息学工具、资助写作和负责任的研究行为的课程。此外，PI 将接受研究技术方面的培训。由他的导师和他的顾问委员会成员的其他专家进行实验，以研究可以增加心脏脂肪酸氧化的机制，并在指导阶段结束后提出治疗心脏脓毒性休克的方法。 PI 将建立一个数据、知识和新技能库，以提高他成功过渡到独立的资格。在 K99 阶段，PI 计划参加一门生物医学信息学课程，一门关于资助写作的课程，另一门关于负责任行为的课程。研究。此外，他还与导师和顾问/合作者制定了培训计划，为他提供有关如何进行超声心动图、在动物模型中诱导心力衰竭、染色质免疫沉淀以及高通量分析工具和方法的技术知识。代表了他将能够转移到自己实验室的有用工具，除了他将获得的新技术之外，拟议的项目还需要他最近才涉及的领域的知识，例如炎症和 Kr¿因此，他的顾问委员会中包括了一些在这些特定领域具有杰出成就的科学家，他们将提供尽可能高水平的指导。他们都受聘于一流的学术部门。同意邀请 PI 介绍他在其研究所内的工作，以便 他收到了广泛的科学受众的意见并扩大了他的科学网络，这将促进他向独立研究职位的过渡，并为他申请 R01 级资金提供坚实的科学基础。该提案的核心问题是：(1)。刺激能量产生可以预防 LPS 介导的心脏功能障碍吗？ (2) LPS 如何导致心脏能量学的变化？ (3) 如何防止 LPS 治疗动物的脂肪酸减少？有两个分支的实验计划。属于 K99 阶段，基于当前提交的初步数据，这组实验旨在确定 PPAR 成为更有效的脂肪酸氧化激活剂的机制。下调，就像脓毒症中发生的情况一样。 此外，PI 将研究脓毒症激活的 JNK 信号通路在 PPAR 表达减少中的作用。 ，一种与脂肪酸氧化密切相关的蛋白质。此外，还将生成一种心肌细胞特异性缺失 KLF5 的新动物模型，并测试其对脓毒症期间心脏功能障碍的抵抗力。此外，这种新型动物模型还将具有高通量的特点。他的计划的第二个分支可能会出现在 R00 阶段，这些干预措施已在初步结果中成功使用，并可预防脓毒症，并将对其治疗心力衰竭的潜力进行探索。机制将在 K99 阶段进行的研究还将确定新的目标，并可能建议应用这些成功的干预措施的新方法，以及高通量分析将表明将用于治疗的新因素。预防脓毒症介导的心脏疾病，以及治疗脂肪酸氧化受损的其他心脏功能障碍、压力超负荷心力衰竭等功能障碍，因此，在接受新技术和心力衰竭模型的培训后，他过渡到独立地位。由于他的能力增强，将得到便利应用预防脓毒症相关心脏功能障碍和压力超负荷心力衰竭的方法，旨在为这些疾病提供新的治疗方法总体而言，当前的提案将为 PI 提供新的知识和有用的工具，以继续在分子心脏病学和应激领域开展独立职业。他的培训计划旨在促进在哥伦比亚大学医学系的杰出环境中完美地生成数据，以及 PI 熟悉现代生物医学研究工具，并将其转移到他的独立实验室。他的申请K99R00 奖将导致新机制的精确定义，这些机制影响心脏脂肪酸氧化和 从而将为治疗感染性休克和心力衰竭提供潜在的新疗法。