HSP60, Inflammation and Cardiovascular Disease

HSP60，炎症和心血管疾病

基本信息

批准号：
8300038
负责人：
ANNE A KNOWLTON
金额：
$ 38.5万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-15 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8300038
关键词：
Acute Acute Disease Address Adult Aging Apoptosis Area Binding Blood Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell Death Cell membrane Cell surface Cells Chaperonin 60 Chronic Disease Complex Diabetes Mellitus Disease Funding Generations HSF1 Heart Heart failure Heat shock proteins Heat-Shock Response Heat-Shock Transcription Factor 2 In Vitro Individual Inflammation Inflammatory Injury Interleukin-1 Investigation Knock-out Knockout Mice Lead Link Mediating Membrane Modality Modeling Patients Pharmaceutical Preparations Plasma Population Post-Translational Protein Processing Proteins Rattus Reporting Role Sepsis Series Signal Pathway Signal Transduction Source Stimulus Stress Surface TLR4 gene TNF gene Toxic effect Work caspase-3 cytokine design extracellular heart cell in vivo inhibitor/antagonist novel therapeutic intervention prevent protein complex protein expression receptor research study toll-like receptor 4 trafficking transcription factor

项目摘要

DESCRIPTION (provided by applicant): Previously we have shown that extracellular (ex) heat shock protein (HSP)60 causes cardiac myocyte apoptosis and the synthesis of TNF and IL-1$. Blocking toll-like receptor (TLR)4 decreased, but did not abolish apoptosis, suggesting that the interaction of HSP60 with TLR4 is complex and involves other proteins. Our over-arching hypothesis is that HSP60 can cause apoptosis and inflammation, and this is associated with abnormal expression, distribution or post-translational modification of HSP60. We will expand our investigation in this important area with 3 specific aims designed to further define the role of HSP60 in heart failure and other cardiovascular disease. SA1 - Investigate the mechanism(s) of exHSP60 mediated apoptosis and inflammation. We will extend our investigation of TLR4 in exHSP60 signaling, determine whether, Eritoran, an inhibitor of TLR4, can reduce apoptosis in vitro and in vivo, and further characterize plasma membrane associated HSP60. SA2 - Investigate extracellular HSP60 trafficking and the role of post-translational modification in its toxicity. We hypothesize that post-translational modifications of HSP60 influence its localization and its extracellular toxicity. Studies have found high levels of HSP60 in the blood of patients with diabetes and other diseases. We will investigate the role of post- translational modifications as well as exosomes in the toxicity of this HSP60. Second we will examine the source of membrane associated HSP60. SA3 - Investigate the role of HSP60 in Repetitive Injury and the Heat Shock Paradox - The heat shock response is protective, and yet, when the heat shock response is induced after an inflammatory stress, rather than protection, increased injury occurs, hence. We found that HSP60 is increased after inflammation followed by heat shock, but not when the order of these stimuli is reversed. This increase in HSP60 is associated with increased apoptosis. In addition, blocking activated heat shock factor (HSF) decreased apoptosis. We will investigate the role of HSF1 and 2 in the heat shock paradox with selective knockout models. HSP60's role in the heat shock paradox will be studied by examining its cellular localization and manipulating its expression. The planned work will expand the PI's investigation of HSP60 and its role in cardiovascular inflammation and apoptosis and has the potential to lead to new therapeutic approaches to heart failure.

描述（申请人提供）：之前我们已经证明细胞外（ex）热休克蛋白（HSP）60导致心肌细胞凋亡以及TNF和IL-1$的合成。阻断 Toll 样受体 (TLR)4 会减少细胞凋亡，但不会消除细胞凋亡，这表明 HSP60 与 TLR4 的相互作用很复杂，并涉及其他蛋白质。我们的首要假设是 HSP60 可以引起细胞凋亡和炎症，这与 HSP60 的异常表达、分布或翻译后修饰有关。我们将通过 3 个具体目标扩大这一重要领域的研究，旨在进一步明确 HSP60 在心力衰竭和其他心血管疾病中的作用。 SA1 - 研究 exHSP60 介导的细胞凋亡和炎症的机制。我们将扩展对 TLR4 在 exHSP60 信号传导中的研究，确定 TLR4 抑制剂 Eritoran 是否可以在体外和体内减少细胞凋亡，并进一步表征质膜相关的 HSP60。 SA2 - 研究细胞外 HSP60 运输以及翻译后修饰对其毒性的作用。我们假设 HSP60 的翻译后修饰影响其定位及其细胞外毒性。研究发现，糖尿病和其他疾病患者的血液中 HSP60 水平较高。我们将研究翻译后修饰以及外泌体在该 HSP60 毒性中的作用。其次，我们将检查膜相关 HSP60 的来源。 SA3 - 研究 HSP60 在重复性损伤和热休克悖论中的作用 - 热休克反应是保护性的，然而，当炎症应激后诱导热休克反应而不是保护时，就会增加损伤，因此。我们发现，在炎症和热休克后，HSP60 会增加，但当这些刺激的顺序颠倒时，HSP60 不会增加。 HSP60 的增加与细胞凋亡的增加相关。此外，阻断激活的热休克因子（HSF）可减少细胞凋亡。我们将通过选择性敲除模型研究 HSF1 和 2 在热休克悖论中的作用。 HSP60 在热休克悖论中的作用将通过检查其细胞定位和操纵其表达来研究。计划中的工作将扩大 PI 对 HSP60 及其在心血管炎症和细胞凋亡中的作用的研究，并有可能开发出治疗心力衰竭的新方法。