VASCULAR ANTI-INFLAMMATORY ACTIONS OF HSP90 INHIBITORS

HSP90 抑制剂的血管抗炎作用

• 批准号: 8426147
• 负责人: John D Catravas
• 金额: $ 15.45万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8426147
• 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

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.

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的副作用限制了其在严重情况下的广泛使用。相反，单靶点抗炎药（如COX抑制剂）没有严重的副作用，但缺乏广谱抗炎活性。显然，获得多靶点、强效、副作用小的抗炎药对心血管疾病的预防和治疗具有重要意义。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预处理都可以通过大大延长生存期、减少或消除全身和终末器官炎症、减轻毛细血管超通透性和恢复正常的终末器官功能来显著保护脓毒症小鼠。初步数据进一步表明，在培养中，这些hsp90抑制剂可以预防和恢复由直接应用几种促炎介质引起的内皮细胞超通透性。这些效应背后的机制尚不清楚。由于hsp90抑制剂最近完成了癌症的I期和II期试验，显示出低发病率和严重的副作用，它们代表了临床有用的抗炎药物的令人兴奋的新可能性。本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抑制剂的抗炎作用主要是由于其选择性多靶向和抑制炎症组织中与hsp90相关的pp60c-src、GSK-32和I:K1，从而减少pp60c-src依赖性内皮肌动蛋白应激纤维的形成，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NF: B功能的降低。总之，这些行动可以减少炎症，防止器官衰竭，恢复主要器官的功能。我们将在两种小鼠炎症模型中验证这一假设，一种是急性（LPS），一种是慢性（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，快速转化为临床实践的新型抗炎药物的可能性应该具有吸引力和高度优先考虑。