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

靶向 PERK：一种缓解血管手术后内膜增生的内皮保护性无支架策略

• 批准号: 10320643
• 负责人: SHAOQIN GONG
• 金额: $ 63.45万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320643
• 关键词: Affect; Angioplasty; Animal Model; Arteries; Attenuated; Automobile Driving; Biological; Biomedical Engineering; Biomimetics; Blood Platelets; Blood Vessels; Blood coagulation; Bypass; Cardiovascular Diseases; Cells; Clinical; Coagulation Process; Data; Development; Drug Delivery Systems; Drug Kinetics; Endothelial Cells; Endothelium; Formulation; Functional disorder; Goals; Growth; Hand; Home; Hyperplasia; Impairment; Implant; Intravenous; Knock-out; Lead; Lesion; Leukocytes; Link; Mediating; Medical; Membrane; Mesenchymal Stem Cells; Methods; Modeling; Molecular Target; Morbidity - disease rate; Mus; Operative Surgical Procedures; Outcome; Patients; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Pre-Clinical Model; Prevention; Research; Risk; Role; STAT3 gene; Sirolimus; Smooth Muscle Myocytes; Source; Stents; Surgeon; Testing; Therapeutic; Thrombosis; Toxic effect; Vascular Diseases; antiproliferative drugs; attenuation; base; biological adaptation to stress; cell type; cost; drug release profile; effective therapy; experimental study; improved; inhibitor/antagonist; injured; innovation; intravenous injection; mortality; nanocluster; nanotechnology platform; new therapeutic target; novel; novel therapeutics; pre-clinical; preclinical development; preclinical evaluation; preservation; prevent; prototype; reconstruction; repaired; stem cell exosomes; targeted delivery; targeted treatment; thrombogenesis

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

项目摘要 血管重建术，如血管成形术和旁路术，经常由于新生内膜增生（IH）而失败， 使血管腔变窄。功能障碍的平滑肌细胞（SMC）是血管平滑肌细胞的主要成分。 新生内膜损伤;邻近内皮细胞（EC）的功能障碍不仅有助于IH， 血栓形成或凝血目前用于IH-衰减的临床方法依赖于抗增殖药物， 在血管成形术后植入支架进行输送。由于药物（例如，雷帕霉素）和支架植入促进剂 由于EC功能障碍，药物洗脱支架的临床结局受到影响，并且还因以下因素而复杂化： 血栓形成风险。解决这一重大医疗问题已成为一项重大挑战， 药物和输送方法的创新。 我们有了一个令人兴奋的初步发现：抑制一种叫做PERK的应激反应激酶 消除SMC和EC功能障碍，并有效减轻IH，而不影响 临床前血管成形术模型中裸露的动脉。我们的中心假设是，PERK是一个共同的目标， 不仅是SMC而且是EC的驱动功能障碍。我们进一步期望PERK抑制剂的无支架递送 将为IH的安全有效治疗提供一种内皮保护方法。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EC功能障碍 在IH期间。为此，我们将PERK确定为主要靶点，抑制PERK可减轻功能障碍 两种细胞类型和IH。在Specific Aim-2中，我们将通过靶向治疗开发无支架治疗策略。 血管内输送以缓解IH。为此，我们创建了一个仿生纳米平台原型， 实现PERK抑制剂靶向发生IH的受损动脉的无支架递送。 这是一个范式转变的建议，因为它融合了药物和药物输送的创新 旨在改善IH治疗的策略。与目前的药物（雷帕霉素）相比， 毒性，PERK抑制阻断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，支架- PERK抑制剂的自由血管内递送将使用仿生纳米簇（涂覆有 生物膜），有效地定位在受伤的动脉上。这项研究的最终成果将是 一种安全有效治疗IH的无血栓形成/无支架新治疗模式。等 治疗预计将大大降低死亡率，发病率，并在数百万的巨大成本， 易患IH相关闭塞性血管疾病的美国患者。 1