HSPs, Inflammatory Response and Cardiovascular Disease

热休克蛋白、炎症反应和心血管疾病

• 批准号: 7261175
• 负责人: ANNE A KNOWLTON
• 金额: $ 29.07万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7261175
• 关键词: Address; Adult; Antibodies; Antigens; Apoptosis; Apoptotic; Binding; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Death; Development; Experimental Designs; Goals; Heart; Heart failure; Heat shock proteins; Heat-Shock Response; Immune system; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Ligands; MAPK3 gene; Mediator of activation protein; Methods; Modeling; Modification; Molecular; Muscle Cells; NF-kappa B; Phosphorylation; Phosphotransferases; Physiological; Plasma; Population; Production; Proteins; Published Comment; RNA; Regulation; Research; Research Personnel; Role; Side; Site; Stimulus; Stress; Toll-like receptors; Tumor Necrosis Factor-alpha; UC01; Work; cytokine; extracellular; human TNF protein; insight; macrophage; prevent; programs; protein expression; research study; response to injury; toll-like receptor 4; transcription factor

DESCRIPTION (provided by applicant): This proposal addresses a paradigm shift: that extracellular heat shock proteins (HSP) are pro-inflammatory and pro-apoptotic. HSPs prevent or ameliorate injury; however, there is evidence of a pro-inflammatory side to these proteins. Extracellular HSP60 is activates the innate immune system via the toll-like receptors (TLR), leading to the production of cytokines. Antibodies to HSPs are found in the population, and more prevalent in those with cardiovascular disease, as is the presence of HSP60 in the plasma. Induction of the heat shock response with expression of HSPs in the setting of a pre-existing inflammatory injury, results not in protection, but in cell death. We hypothesize that extracellular HSP60 can function as an inducer of inflammation in the cardiovascular system, and that inflammation can paradoxically inhibit the HSP response to injury, or convert the induction of the heat shock response from protective to harmful. We will address this in 3 Specific Aims: 1. Define the role of HSP60 in cardiac inflammation- HSP60 is a ligand forTLR-4 and can activate the innate immune system resulting in the production of cytokines. In adult cardiac myocytes, we will characterize the binding of HSP60, define the pro-apoptotic effect of HSP60 and as well as its effect on cytokine production. 2. Determine how repetitive injury interacts with the heat shock response to convert it from protective to pro-apoptotic- Sequential injury by an inflammatory stimulus followed by a HSP inducing injury results in apoptosis rather than protection. We have found that inflammatory stimuli, including TNF-alpha and HSP60, induce apoptosis, and when followed by heat shock, greatly increase apoptosis. Thus, HSP60 can prime the cardiovascular system for injury. Experiments will study the effect of TNF-alpha followed by heat shock, determine how this disproportionately increases injury, and how HSP60 causes apoptosis. 3. Identify the mechanism (s) leading to increased HSP60 in the failing heart. We hypothesize that HSF-1, a transcription factor for HSPs, is inactivated in heart failure by ERK1 and GSK3, and that increased HSP60 expression is driven by NFKB. In turn, extracellular HSP60 in heart failure causes inflammation and activation of NFKB. Work will address HSF-1 modification and function, and control of HSP expression. The long term goal of the Pi's research is to understand the role of heat shock proteins in cardiac injury, and thus, to achieve further insights into how to prevent as well as treat cardiac injury.

描述（由申请人提供）：该提案解决了范式转移：细胞外热休克蛋白（HSP）是促炎和促凋亡的。 HSP预防或改善损伤；但是，有证据表明这些蛋白质具有促炎的一面。细胞外HSP60通过Toll样受体（TLR）激活先天免疫系统，从而导致细胞因子的产生。在人群中发现了对HSP的抗体，在患有心血管疾病的患者中，血浆中HSP60的存在也更为普遍。在预先存在的炎症性损伤的情况下，HSP的表达诱导热休克反应，不是保护，而是在细胞死亡中。我们假设细胞外HSP60可以充当心血管系统炎症的诱导剂，并且炎症可以矛盾地抑制HSP对损伤的反应，或转化从保护性转化为有害的热冲击反应。我们将在3个具体目标中解决这一点：1。定义HSP60在心脏炎症中的作用-HSP60是配体Fortlr-4，可以激活先天免疫系统，从而导致细胞因子的产生。在成年心肌细胞中，我们将表征HSP60的结合，定义了HSP60的促凋亡作用，及其对细胞因子产生的影响。 2.确定重复损伤与热冲击反应如何相互作用，以通过炎症刺激将其从保护性转化为促凋亡 - 顺序损伤，然后诱导HSP损伤导致细胞凋亡而不是保护。我们发现，包括TNF-Alpha和Hsp60在内的炎症刺激会诱导凋亡，然后在热休克随后会大大增加凋亡。因此，HSP60可以为损伤的心血管系统灌输。实验将研究TNF-Alpha的影响，然后进行热休克的影响，确定这种情况不成比例地增加损伤以及HSP60如何导致凋亡。 3。确定导致HSP60在失败心脏中增加的机制。我们假设HSF-1是HSP的转录因子，ERK1和GSK3在心力衰竭中失活，而增加的HSP60表达是由NFKB驱动的。反过来，心力衰竭的细胞外HSP60会引起NFKB的炎症和激活。工作将解决HSF-1修改和功能，以及HSP表达的控制。 PI研究的长期目标是了解热休克蛋白在心脏损伤中的作用，从而进一步了解如何预防和治疗心脏损伤。