VASCULAR ANTI-INFLAMMATORY ACTIONS OF HSP90 INHIBITORS

HSP90 抑制剂的血管抗炎作用

基本信息

批准号：
7889057
负责人：
John D Catravas
金额：
$ 36.75万
依托单位：
AUGUSTA 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：
2010-04-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7889057
关键词：
Actins Acute Adult Respiratory Distress Syndrome Adverse effects Affinity Anti-Inflammatory Agents Anti-inflammatory Atherosclerosis Attenuated Binding Blood Vessels Blood capillaries Cardiovascular Diseases Cardiovascular system Cell physiology Chronic Client Coronary Restenosis Cyclooxygenase Inhibitors Data Diabetes Mellitus Disease Endothelial Cells Exhibits Functional disorder HSP 90 inhibition Heat-Shock Proteins 90 Hypertension Immunosuppressive Agents In Vitro Incidence Inflammation Inflammation Mediators Malignant Neoplasms Mediating Microtubule Depolymerization Modeling Molecular Chaperones Molecular Conformation Mus Non-Insulin-Dependent Diabetes Mellitus Organ Organ failure Permeability Pharmaceutical Preparations Phase I/II Trial Phase II Clinical Trials Prevention Proteins Regulation Reperfusion Injury Retinal Diseases Severities Stress Fibers Testing Tissues Translating Translations capillary clinical practice dimer direct application in vivo inhibitor/antagonist mortality mouse model novel prevent protein degradation protein folding public health relevance repaired septic tau phosphorylation

项目摘要

DESCRIPTION (provided by applicant): Inflammation is a causative factor in most major cardiovascular diseases, including atherosclerosis, hypertension, acute respiratory distress syndrome (ARDS), diabetes, retinopathy and cancer. While glucocorticosteroids possess strong anti-inflammatory activity, their immunosuppressive and catabolic side-effects restrict their wide-spread use to only severe circumstances. Conversely, single-target anti-inflammatory agents (e.g., COX inhibitors) lack serious side effects but are void of broad-spectrum anti-inflammatory activity. Clearly, the availability of multi-targeted, strong anti-inflammatory agents with limited side effects would be of great significance in the prevention and management of cardiovascular disease. Emerging data suggest that heat shock protein 90 (hsp90) inhibitors may fit this profile. Recently, we demonstrated that pretreatment with either of two hsp90 inhibitors dramatically protects septic mice by greatly prolonging survival, reducing or abolishing systemic and end organ inflammation, attenuating capillary hyper-permeability and restoring normal end organ function. Preliminary data further suggest that these hsp90 inhibitors prevent as well as restore endothelial hyper-permeability induced by direct application of any of several pro-inflammatory mediators, in culture. The mechanism(s) behind these effects remain unclear. Since hsp90 inhibitors have recently completed Phase I and II trials for cancer, demonstrating low incidence and severity of side effects, they represent an exciting new possibility as clinically useful anti- inflammatory drugs. The purpose of this application is to investigate this possibility by exploring a key mechanism behind the anti-inflammatory effects of hsp90 inhibitors. Our overall hypothesis is that the anti-inflammatory effects of hsp90 inhibitors are largely due to their selective multi-targeting and inhibition of hsp90-associated pp60c-src, GSK-32 and I:K1 in inflamed tissues, leading to reduced pp60c-src-dependent formation of endothelial actin stress fibers, reduced GSK-32-dependent tau phosphorylation and microtubule depolymerization, thus preventing and repairing the endothelial barrier dysfunction associated with inflammation. The additional targeting and inhibition of I: 1 function also contributes to reduce NF: B function. Together, these actions reduce inflammation, prevent organ failure and restore major organ function. We will test this hypothesis in two mouse models of inflammation, an acute (i.p. LPS) and a chronic (type 2 diabetes exhibited by Leprdb mice) model. Given the persistent high mortality from cardiovascular disease, the possibility of quickly translating into clinical practice novel anti-inflammatory drugs should be appealing and of high priority. PUBLIC HEALTH RELEVANCE: This proposal aims to uncover the mechanisms behind the recently demonstrated anti-inflammatory effects of inhibitors of heat shock protein 90. Because these drugs have finished Phase II clinical trials and exhibit low side effects translation of these findings from these studies in cardiovascular disease should be expeditious.

描述（由申请人提供）：炎症是大多数主要心血管疾病的致病因素，包括动脉粥样硬化、高血压、急性呼吸窘迫综合征（ARDS）、糖尿病、视网膜病变和癌症。虽然糖皮质激素具有很强的抗炎活性，但其免疫抑制和分解代谢副作用限制了其仅在严重情况下广泛使用。相反，单靶点抗炎药（例如COX抑制剂）缺乏严重的副作用，但缺乏广谱抗炎活性。显然，获得多靶点、强效抗炎药物且副作用有限，对于心血管疾病的预防和治疗具有重要意义。新数据表明热休克蛋白 90 (hsp90) 抑制剂可能符合这一特征。最近，我们证明用两种 hsp90 抑制剂中的任何一种进行预处理可显着延长存活期、减少或消除全身和终末器官炎症、减弱毛细血管高通透性和恢复正常终末器官功能，从而显着保护脓毒症小鼠。初步数据进一步表明，这些 hsp90 抑制剂可预防并恢复在培养物中直接应用几种促炎介质中的任何一种所诱导的内皮高渗透性。这些影响背后的机制仍不清楚。由于 hsp90 抑制剂最近完成了针对癌症的 I 期和 II 期试验，表明副作用发生率低且严重程度低，因此它们代表了作为临床有用的抗炎药物的令人兴奋的新可能性。本申请的目的是通过探索 hsp90 抑制剂抗炎作用背后的关键机制来研究这种可能性。我们的总体假设是，hsp90抑制剂的抗炎作用很大程度上是由于其选择性多靶点和抑制发炎组织中hsp90相关的pp60c-src、GSK-32和I:K1，导致pp60c-src-减少内皮肌动蛋白应激纤维的依赖性形成，减少 GSK-32 依赖性 tau 磷酸化和微管解聚，从而预防和修复与炎症相关的内皮屏障功能障碍。 I:1 功能的额外靶向和抑制也有助于降低 NF:B 功能。这些作用共同减少炎症、预防器官衰竭并恢复主要器官功能。我们将在两种小鼠炎症模型中测试这一假设，即急性（腹腔注射 LPS）模型和慢性（Leprdb 小鼠表现出的 2 型糖尿病）模型。鉴于心血管疾病的持续高死亡率，将新型抗炎药物快速转化为临床实践的可能性应该是有吸引力且高度优先的。公共健康相关性：本提案旨在揭示最近证明的热休克蛋白 90 抑制剂的抗炎作用背后的机制。因为这些药物已完成 II 期临床试验并表现出较低的副作用，这些结果来自心血管研究的转化病应迅速。