VASCULAR ANTI-INFLAMMATORY ACTIONS OF HSP90 INHIBITORS

描述(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仅在恶劣环境下的广泛使用。相反，单靶点抗炎药(如COX抑制剂)缺乏严重的副作用，但缺乏广谱抗炎活性。显然，多靶点、强抗炎、副作用小的抗炎药物的可获得性在心血管疾病的预防和治疗中具有重要意义。新出现的数据表明，热休克蛋白90(HSP90)抑制剂可能符合这一特征。最近，我们证明了两种HSP90抑制剂中的任何一种都能显著地保护脓毒症小鼠，显著延长小鼠的存活时间，减轻或消除全身和终末器官的炎症，减轻毛细血管的高通透性，并恢复正常的终末器官功能。初步数据进一步表明，这些HSP90抑制剂可以预防和恢复因在培养中直接应用几种促炎介质而导致的内皮高通透性。这些效应背后的机制(S)尚不清楚。由于HSP90抑制剂最近已经完成了癌症的I期和II期试验，显示出低发生率和严重的副作用，它们代表了一种令人兴奋的新的可能性，作为临床上有用的抗炎药物。这项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。我们的总体假设是，HSP90抑制剂的抗炎作用很大程度上是因为它们选择性地多靶向并抑制炎症组织中HSP90相关的pp60c-src、GSK-32和I：K1，导致依赖pp60c-src的内皮肌动蛋白应激纤维的形成减少，减少依赖GSK-32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是导致NF：B功能降低的原因之一。总而言之，这些行动减少炎症，预防器官衰竭，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，急性炎症(I.P.和慢性(Leprdb小鼠表现出的2型糖尿病)模型。鉴于心血管疾病死亡率居高不下，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和高度优先的。

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.