Inflammatory-metabolic Crosstalk in the Myocardium

心肌中的炎症代谢串扰

基本信息

批准号：
8197807
负责人：
Joel David Schilling
金额：
$ 11.9万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-19 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197807
关键词：
Address Advisory Committees Affect Animal Model Apoptosis Area Atherosclerosis Breeding Cardiac Cardiac Myocytes Cardiology Cardiomyopathies Cardiovascular Diseases Cardiovascular system Cause of Death Cells Cessation of life Complement Coupled Development Diabetes Mellitus Diet Disease Doctor of Philosophy Down-Regulation Echocardiography Elements Energy Metabolism Environment Faculty Fellowship Functional disorder Gene Expression Generations Genetic Transcription Grant Heart Heart Diseases Heart failure Immunohistochemistry In Vitro Inflammation Inflammatory Inflammatory Response Insulin Resistance Internal Medicine Knockout Mice Knowledge Lipids Lipopolysaccharides Lipoproteins Manuscripts Mediating Mentors Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Mus Muscle Cells Myocardial Myocardial Infarction Myocardium Nature Neonatal Nuclear Receptors Obesity Palmitates Pathogenesis Pathway interactions Patients Phenotype Physicians Physiological Play Principal Investigator Production Rattus Reactive Oxygen Species Regulatory Pathway Research Research Personnel Research Proposals Residencies Role Saturated Fatty Acids Scientist Severities Signal Pathway Signal Transduction Small Interfering RNA Streptozocin Stress Structure TLR2 gene TLR4 gene Techniques Testing Tetracyclines Toll-like receptors Training Training Programs Trans-Activators Transcription Coactivator Transcriptional Regulation Transgenic Mice Transgenic Organisms Transplantation Universities Washington Writing career chemokine cytokine defined contribution diabetic diabetic cardiomyopathy diabetic patient heart metabolism in vivo inflammatory modulation insight lipid metabolism loss of function mouse model novel programs public health relevance receptor receptor-mediated signaling skills toll-like receptor 4

项目摘要

DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for developing the skills necessary to become a successful cardiovascular investigator focused on heart failure. The principal investigator has completed MD/PhD training, structured residency training in internal medicine and fellowship training in cardiology and heart failure/transplant at Washington University. He plans to expand his scientific skills to facilitate an integrative career as a physician scientist in the rich academic environment existing at Washington University. The objectives of this research proposal include furthering the principal investigator's experimental technique repertoire, expanding manuscript and grant writing skills, and developing an expertise in the areas of cardiac energy and lipid metabolism to augment his knowledge of inflammatory responses. Dr. Jean Schaffer will mentor the investigator's scientific development. She is a recognized leader in the field of diabetic cardiovascular disease and lipotoxicity, and has an excellent mentoring record. Dr. Dan Kelly, a co-mentor for this proposal is an established investigator in the field of cardiac metabolism in heart failure and diabetes with particular expertise in transcriptional regulation of metabolic and mitochondrial pathways in the heart. An advisory committee consisting of three outstanding physician scientists with relevant expertise will provide additional scientific and career guidance. The proposed research will investigate the molecular crosstalk between Toll-like Receptor (TLR)-mediated inflammation and myocardial metabolism as it pertains to cardiac dysfunction in diabetes and obesity. Specific aim #1 will define the effects of LPS-induced TLR4-mediated inflammation on myocardial metabolism with an emphasis on inflammatory modulation of the nuclear receptor coactivators PGC-1 and , which function as master regulators of energy metabolism in the heart. Specific Aim #2 will address the role of TLRs in cardiac lipotoxicity, a key feature of heart failure in diabetics. This will be accomplished by characterizing the cardiac phenotype of the lipotoxic MHC-ACS transgenic mouse bred into TLR4 and TLR4/2 null backgrounds. These results will be complemented with mechanistic studies using TLR4 and TLR2 deficient cells stimulated with the saturated fatty acid palmitate. Specific Aim #3 will use non-transgenic animal models of diabetes and diet- induced insulin resistance in TLR4-/- and TLR4/2-/- mice to evaluate the role of TLRs in the cardiac phenotype associated with these disease states. Together these studies will help define the contribution of TLR-mediated signaling pathways to cardiac dysfunction in diabetes and will provide significant mechanistic insight into inflammatory-metabolic crosstalk in the myocardium. The Cardiology Division at Washington University provides a supportive environment for training physician- scientists. The diverse scientific expertise of the faculty coupled with the large number of successful physician scientists creates an ideal situation for the principal investigator to develop an independent research program. PUBLIC HEALTH RELEVANCE: Diabetes is an extremely common disease in the U.S. and the number of people with this disorder continues to grow. Patients with diabetes have higher rates of early death than patients without diabetes, largely due to heart disease. In addition heart attacks, diabetes also causes the heart muscle to weaken, leading to heart failure. It is not known precisely why patients with diabetes develop heart failure, but inflammation may play a key role. This proposal will evaluate how the inflammatory response affects the heart and how it may contribute to the heart failure that develops in diabetic patients.

描述（由申请人提供）：该提案描述了一项为期5年的培训计划，以开发成为一名致力于心力衰竭的心血管调查员所需的技能。首席研究人员已完成了华盛顿大学心脏病学和心力衰竭/心力衰竭的内科和奖学金培训的MD/PHD培训，结构化居住培训。他计划扩大自己的科学技能，以促进华盛顿大学现有的丰富学术环境中的医师科学家的综合事业。这项研究建议的目标包括进一步发展主要研究者的实验技术曲目，扩大手稿和授予写作技巧，以及在心脏能量和脂质代谢领域发展专业知识，以增强他对炎症反应的了解。让·沙弗（Jean Schaffer）博士将指导研究人员的科学发展。她是糖尿病心血管疾病和脂肪毒性领域的公认领导者，并具有出色的指导记录。该提案的联合学者丹·凯利（Dan Kelly）博士是心力衰竭和糖尿病领域的一名既定研究者，在心脏中的代谢和线粒体途径的转录调节方面具有特殊的专业知识。由三位具有相关专业知识的杰出医师科学家组成的咨询委员会将提供更多的科学和职业指导。拟议的研究将研究类似于Toll样受体（TLR）介导的炎症和心肌代谢之间的分子串扰，因为它与糖尿病和肥胖症中心脏功能障碍有关。具体目的＃1将定义LPS诱导的TLR4介导的炎症对心肌代谢的影响，重点是对核受体共激活剂PGC-1的炎症调节，并且起着心脏能量代谢能量代谢的主要调节剂。特定的目标＃2将解决TLR在心脏脂肪毒性中的作用，这是糖尿病患者心力衰竭的关键特征。这将通过表征育成TLR4和TLR4/2无效背景的脂蛋白毒性MHC-ACS转基因小鼠的心脏表型来实现。这些结果将与使用饱和脂肪酸棕榈酸盐刺激的TLR4和TLR2缺陷细胞相互补充。特定的目标＃3将使用TLR4 - / - 和TLR4/2 - / - 小鼠中糖尿病的非转基因动物模型以及饮食诱导的胰岛素抵抗来评估TLR在与这些疾病状态相关的心脏表型中的作用。这些研究共同有助于定义TLR介导的信号通路对糖尿病中心脏功能障碍的贡献，并将为心肌中炎性代谢串扰提供重要的机械洞察力。华盛顿大学心脏病学系为培训医师科学家提供了支持环境。该教师的多样化科学专业知识以及大量成功的医师科学家为主要研究者制定了一个独立研究计划的理想情况。公共卫生相关性：在美国，糖尿病是一种极为常见的疾病，这种疾病的人数继续增加。糖尿病患者的早期死亡率比没有糖尿病的患者高，这主要是由于心脏病。此外，心脏病发作，糖尿病还会导致心肌减弱，导致心力衰竭。尚不清楚为什么糖尿病患者会出现心力衰竭，而炎症可能起关键作用。该提案将评估炎症反应如何影响心脏以及它如何促进糖尿病患者发展的心力衰竭。