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：
8231387
负责人：
John D Catravas
金额：
$ 36.38万
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/8231387
关键词：
17-(Allylamino)-17-demethoxygeldanamycin 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 Fluorescein-5-isothiocyanate Functional disorder HSP 90 inhibition Heat-Shock Proteins 90 Histone Deacetylase 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原因，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。尽管糖皮质激素具有强大的抗炎活性，但它们的免疫抑制和分解代谢副作用限制了它们的广泛使用，仅对严重的情况。相反，单靶性抗炎剂（例如Cox抑制剂）缺乏严重的副作用，但没有广谱的抗炎活性。显然，具有有限副作用的多靶标，强大的抗炎药的可用性对于预防和管理心血管疾病将具有重要意义。新兴数据表明，热休克蛋白90（HSP90）抑制剂可能符合此曲线。最近，我们证明了两个HSP90抑制剂中的任何一个都可以通过大大延长生存率，减少或废除系统性和最终器官炎症，衰减毛细血管超渗透性和恢复正常最终器官功能，从而极大地保护化粪池小鼠。初步数据进一步表明，这些HSP90抑制剂预防以及通过在培养中直接应用几种促炎性介体中的任何一种引起的内皮内皮过度过度性。这些作用背后的机制尚不清楚。由于HSP90抑制剂最近已经完成了癌症的I和II期试验，表现出副作用的发病率和严重程度，因此作为临床上有用的抗炎药，它们代表了令人兴奋的新可能性。该应用的目的是通过探索HSP90抑制剂抗炎作用背后的关键机制来研究这种可能性。 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-内皮肌动蛋白应激纤维的依赖性形成，依赖GSK-32依赖性的Tau磷酸化和微管解聚，从而防止和修复与炎症相关的内皮屏障功能障碍。 I：1功能的其他靶向和抑制也有助于降低NF：B功能。这些动作共同减少了炎症，防止器官衰竭并恢复主要器官功能。我们将在两种炎症的小鼠模型，急性（i.p. LPS）和慢性（LEPRDB小鼠表现出的2型糖尿病）模型中检验该假设。鉴于心血管疾病的持续高死亡率，可以快速转化为临床实践的新型抗炎药的可能性应具有吸引力和优先级。公共卫生相关性：该提案旨在揭示最近证明的热休克蛋白抑制剂90的抗炎作用背后的机制。因为这些药物已经完成了II期临床试验，并从心血管腔中表现出这些发现的低副作用翻译。疾病应该是迅速的。