Targeting PERK: An Endothelium-Protective Stent-Free Strategy for Mitigation of Intimal Hyperplasia After Vascular Surgery

项目摘要 血管重建，如血管成形术和搭桥术，通常由于新生内膜增生(IH)而失败 使血管管腔变窄。功能障碍的平滑肌细胞是血管内皮细胞的主要成分。 邻近血管内皮细胞(ECs)功能障碍不仅参与了IH的发生，而且还促进了 血栓形成或凝血。目前临床上对IH-衰减剂的治疗依赖于抗增殖药物和 血管成形术后植入支架分娩。因为药物(如雷帕霉素)和支架置入术都促进 EC功能障碍，药物洗脱支架的临床结果受到影响，还会并发 血栓形成的风险。解决这一重大医学问题一直是它所需要的最大挑战 在药物和给药方法方面都有创新。 我们有了一个令人兴奋的初步发现：抑制一种名为PERK的应激反应激酶 消除SMC和EC功能障碍，有效缓解IH，不影响血管内皮细胞修复 临床前血管成形术模型中的裸露动脉。我们的中心假设是，津贴是一个共同的目标 不仅是SMC的功能障碍，还有ECs的功能障碍。我们进一步预计，无支架传递的PERK抑制剂 将为IH的安全有效治疗提供一种内皮保护途径。因此，在 具体目标-1，我们将定义一个共同的分子靶点，促进SMC和ECs的功能障碍 在IH期间。为此，我们已将PERK确定为主要靶点，其抑制作用可缓解功能障碍 这两种细胞类型和IH。在特定的目标-2中，我们将开发一种无支架的治疗策略，通过靶向 血管内给药以减轻IH。为此，我们创建了一个仿生纳米平台的原型 实现PERK抑制剂的无支架输送，靶向发生IH的受损动脉。 这是一个改变范式的提议，因为它将药物和药物输送方面的创新结合在一起 旨在改善对IH的治疗的战略。与目前的药物(雷帕霉素)不同，雷帕霉素是一种新型的药物。 毒性，PERK抑制可阻止SMC功能障碍(增殖和去分化)和EC功能障碍 (生长受损和血栓形成)。此外，与目前的支架植入方法截然不同的是，支架- 使用仿生纳米簇(包覆有 生物膜)，有效地附着在受损的动脉上。这项研究的最终成果将是 一种非血栓形成/无支架的安全有效治疗IH的新治疗范例。是这样的 预计治疗将显著降低数百万人的死亡率、发病率和巨大成本 在美国，易患高血压相关闭塞性血管疾病的患者。 1

Project Summary Vascular reconstructions, such as angioplasty and bypass, often fail due to neointimal hyperplasia (IH) that re- narrows the vessel lumen. Dysfunctional smooth muscle cells (SMCs) are the major constituents of the neointimal lesion; dysfunction of adjacent endothelial cells (ECs) not only contributes to IH but also promotes thrombosis or clotting. The current clinical method for IH-attenuation relies on anti-proliferative drugs and delivery with a stent implanted following angioplasty. As both the drug (e.g., rapamycin) and stenting promote EC dysfunction, the clinical outcome of drug-eluting stents is compromised and also complicated by thrombogenic risks. It has been a paramount challenge to solve this major medical problem as it requires innovations in both drug and delivery methods. We have made an exciting preliminary finding: inhibition of a stress-response kinase called PERK abrogates both SMC and EC dysfunction, and effectively mitigates IH, without affecting endothelial repair of denuded arteries in a preclinical angioplasty model. Our central hypothesis is that PERK is a common target driving dysfunction of not only SMCs but also ECs. We further expect that stent-free delivery of PERK inhibitor will provide an endothelium-protective approach for the safe and effective treatment of IH. Therefore, in Specific Aim-1, we will define a common molecular target that promotes dysfunction in both SMCs and ECs during IH. To this end, we have identified PERK as a lead target, the inhibition of which mitigates dysfunction of both cell types and IH. In Specific Aim-2, we will develop a stent-free therapeutic strategy via targeted endovascular delivery to mitigate IH. For this aim, we have created a prototype biomimetic nanoplatform to achieve stent-free delivery of PERK inhibitor targeted to injured arteries where IH occurs. This is a paradigm-shifting proposal because it conflates innovations in both drug and drug delivery strategies aimed at improving treatment for IH. In contrast to the status quo drug (rapamycin) which is EC- toxic, PERK inhibition blocks both SMC dysfunction (proliferation and de-differentiation) and EC dysfunction (impaired growth and thrombogenesis). Moreover, drastically different from the current stenting method, stent- free endovascular delivery of PERK inhibitor will be achieved using biomimetic nanoclusters (coated with biological membranes) that effectively home in on injured arteries. The ultimate product of this research will be a non-thrombogenic/stent-free new therapeutic paradigm for the safe and effective treatment of IH. Such treatment is expected to significantly reduce the mortality, morbidity, and tremendous costs among millions of patients in the US who are predisposed to IH-associated occluding vascular diseases. 1