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

基本信息

批准号：
9088504
负责人：
Konstantinos Drosatos
金额：
$ 23.64万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
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：
2012-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9088504
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 Computer Simulation Congestive Heart Failure 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 Myocardial dysfunction N-terminal Nuclear Receptors Organ Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Phase Positioning Attribute Precipitation Principal Investigator Production Proteins Research Research Technics Resistance Role Scientist Sepsis Septic Shock Signal Pathway Signal Transduction Small Interfering RNA Stress TLR4 gene Techniques Technology Testing Therapeutic Training Universities Work Writing adenoviral-mediated 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 receptor recombinant adenovirus research study responsible research conduct rosiglitazone septic skills successful intervention tool transcription factor

项目摘要

SUMMARY 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.

概括拟议的研究将促进校长的教育和职业目标的改善研究人员（PI）。此外，PI将研究降低心脏脂肪酸的机制败血症期间的氧化。 PI在最初两年（K99阶段）制定了教育计划拟议的研究。该计划包括有关生物信息学工具的课程，赠款写作和负责任的行为研究。此外，PI将由其心理和其他专家的研究技术培训他的咨询委员会成员。 PI将执行实验，以调查可以增加心脏脂肪酸的氧化，并将提出治疗心脏化为治疗方法震惊。在修正阶段结束后，PI将建立一系列数据，知识和新的可以增强他成功过渡到独立的资格的技能。在K99阶段，PI计划参加一门有关生物医学信息学的课程，其中一门关于赠款写作以及负责任的研究行为。此外，他还以心理制定了培训计划他的顾问/合作者将为他提供有关如何执行的技术知识超声心动图，动物模型中心力衰竭的诱导，染色质免疫沉淀和高吞吐量分析工具和方法。这些技术代表了他将能够转移的有用工具到他自己的实验室。除了他将获得的新技术外，拟议的项目还需要知识他直到最近才与之相关的领域，例如感染和类似Krppel的因子生物学。因此，他在其顾问委员会中包括了许多有出色职业的科学家将提供最高水平的指导的特定领域。他所有的顾问都被顶级雇用缺口学术部门。他们已同意邀请PI在其机构中介绍他的作品，因此他收到了广泛的科学观众的意见，并扩大了他的科学网络。这将促进他的过渡到独立的研究职位，并为他提供了强大的科学基础申请R01级资金。提案核心问题是：（1）能源生产可以预防LPS介导的心脏功能障碍？（2）LPS如何导致心脏能量的变化？（3）如何减少粮农组织在LPS治疗的动物中阻止了吗？为了解决这些问题，PI设计了一个实验计划有两个分支。第一个属于K99阶段，并基于当前的初步数据提交。这组实验旨在确定使PPAR成为更潜在激活剂的机制当PPAR下调时，脂肪酸氧化的氧化，就像在败血症中发生一样。另外，PI将调查 JNK信号通路的作用是由败血症激活的，在PPAR的表达降低中与脂肪酸氧化密切相关的蛋白质。此外，一种新的动物模型 KLF5的心肌细胞特异性删除将产生并测试对心脏功能障碍的抗性在败血症期间。此外，这种新型动物模型将以高吞吐量分析方法来表征可能会出现新目标。他计划的第二个分支落入R00阶段。某些干预措施在初步结果中已成功使用的，并且将探索败血症心力衰竭的治疗潜力。阐明将在K99中研究的机制阶段还将确定新的靶标，并可能提出败血症治疗的新方法。应用在这些成功的干预措施中，以及高通量分析正在进行的新因素表示将用于防止败血症介导的心脏功能障碍，并治疗其他情况脂肪酸氧化受损的心脏功能障碍，例如压力超负荷心力衰竭。因此，之后他在新技术和产生心力衰竭模型中的培训，转变为独立职位由于他的能力增加了防止败血症相关心脏的方法，因此将准备准备功能障碍和压力超负荷心力衰竭，旨在为这些疾病提供新的治疗方法。总体而言，当前的建议将为PI配备新颖的知识和有用的工具，以继续分子心脏病学和压力信号传导的独立职业。他的培训计划被设计为促进医学系的重要环境中完美的数据生产哥伦比亚大学以及PI使用现代生物医学研究工具的收购转移到他的独立实验室。批准他申请K99R00奖项将导致新机制的精确定义，这些机制影响心脏脂肪酸氧化，从而提供潜在的新疗法用于治疗败血性休克和心力衰竭。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Amyloid-Beta (1-40) Peptide and Subclinical Cardiovascular Disease.

β-淀粉样蛋白 (1-40) 肽和亚临床心血管疾病。

DOI：
10.1016/j.jacc.2018.06.027
发表时间：
2018
期刊：
Journal of the American College of Cardiology
影响因子：
24
作者：
Stamatelopoulos,Kimon;Pol,ChristineJ;Ayers,Colby;Georgiopoulos,Georgios;Gatsiou,Aikaterini;Brilakis,EmmanouilS;Khera,Amit;Drosatos,Konstantinos;deLemos,JamesA;Stellos,Konstantinos
通讯作者：
Stellos,Konstantinos

Savings precede spending: fatty acid utilization relies on triglyceride formation for cardiac energetics.