VASCULAR ANTI-INFLAMMATORY ACTIONS OF HSP90 INHIBITORS

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、视网膜病和癌症。虽然糖皮质激素具有强烈的抗炎活性，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的广泛使用。相反，单靶点抗炎药（例如，考克斯抑制剂）没有严重的副作用，但没有广谱抗炎活性。显然，多靶点，强抗炎药的可用性与有限的副作用，将在预防和管理心血管疾病的重要意义。新出现的数据表明，热休克蛋白90（hsp 90）抑制剂可能适合这种情况。最近，我们证明了两种热休克蛋白90抑制剂的预处理可以显著延长脓毒症小鼠的存活时间，减少或消除全身和终末器官的炎症，减弱毛细血管通透性过高，恢复正常的终末器官功能。初步数据进一步表明，这些hsp 90抑制剂预防以及恢复内皮细胞高渗透性诱导的直接应用的任何几个促炎介质，在文化。这些影响背后的机制仍不清楚。由于热休克蛋白90抑制剂最近完成了癌症的I期和II期试验，证明了低发生率和副作用的严重性，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hsp 90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，hsp 90抑制剂的抗炎作用很大程度上是由于其选择性多靶向和抑制炎症组织中与hsp 90相关的pp 60 c-src、GSK-32和I：K1，导致减少pp 60 c-src依赖的内皮肌动蛋白应力纤维形成，减少GSK-32依赖的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。总之，这些行动减少炎症，防止器官衰竭和恢复主要器官功能。我们将在两种小鼠炎症模型中检验这一假设，即急性（腹腔内LPS）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，迅速将新型抗炎药物转化为临床实践的可能性应该是有吸引力的，并具有高度优先性。 公共卫生相关性：该提案旨在揭示最近证明的热休克蛋白90抑制剂抗炎作用背后的机制。由于这些药物已经完成了II期临床试验，并且显示出低副作用，因此这些研究结果在心血管疾病中的转化应该是迅速的。

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.