HSPs, Inflammatory Response and Cardiovascular Disease

热休克蛋白、炎症反应和心血管疾病

基本信息

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
项目类别：
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

项目摘要

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变：细胞外热休克蛋白（HSP）具有促炎性和促凋亡性。 HSP 可预防或减轻损伤；然而，有证据表明这些蛋白质具有促炎作用。细胞外 HSP60 通过 Toll 样受体 (TLR) 激活先天免疫系统，从而产生细胞因子。 HSP 抗体存在于人群中，并且在患有心血管疾病的人群中更为普遍，血浆中也存在 HSP60。在预先存在的炎症损伤的情况下，通过表达 HSP 来诱导热休克反应，不会导致保护，而是导致细胞死亡。我们假设细胞外 HSP60 可以作为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，或者将热休克反应的诱导从保护性转变为有害性。我们将在 3 个具体目标中解决这个问题： 1. 定义 HSP60 在心脏炎症中的作用 - HSP60 是 TLR-4 的配体，可以激活先天免疫系统，从而产生细胞因子。在成年心肌细胞中，我们将表征 HSP60 的结合，定义 HSP60 的促凋亡作用及其对细胞因子产生的影响。 2. 确定重复性损伤如何与热休克反应相互作用，将其从保护性转化为促凋亡性。炎症刺激继之以 HSP 诱导损伤的顺序损伤会导致细胞凋亡，而不是保护。我们发现炎症刺激，包括 TNF-α 和 HSP60，会诱导细胞凋亡，而当热激后，会大大增加细胞凋亡。因此，HSP60 可以使心血管系统做好损伤准备。实验将研究热休克后 TNF-α 的影响，确定其如何不成比例地增加损伤，以及 HSP60 如何导致细胞凋亡。 3. 确定导致衰竭心脏中 HSP60 增加的机制。我们假设 HSF-1（HSP 的转录因子）在心力衰竭中被 ERK1 和 GSK3 灭活，并且 HSP60 表达增加是由 NFKB 驱动的。反过来，心力衰竭中的细胞外 HSP60 会引起炎症和 NFKB 激活。工作将解决 HSF-1 的修饰和功能，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。