Molecular Targeting of Plaque Angiogenesis in Diabetes

描述(申请人提供)：小口径血管网络，称为血管，局限于主要大口径血管的外部中层和外膜层；然而，在动脉粥样硬化和其他脉管炎的情况下，这些血管增殖并侵入内膜。越来越多的数据表明，斑块新生血管的通透性、炎细胞募集和出血特性促进了动脉粥样硬化及其并发症的发生。侵袭动脉粥样硬化病变的新生血管网络也可能是药物进入病变动脉的更有效的门户，以控制其闭塞和斑块的不稳定性。在糖尿病中，我们最近发现斑块获得新生血管的趋势显著增加，并加速动脉粥样硬化。因此，糖尿病斑块新生血管上显示的分子的特征可以识别发生在这种独特的微血管内皮细胞上的重要配体/受体相互作用，并介导病理功能。这些分子靶点可以用来为病理性新生血管输送分子显像剂或药物，并将其对正常动脉的影响降至最低。我们假设血管新生斑块毛细血管显示独特的分子，促进糖尿病的动脉粥样硬化，这将有助于了解和修改其功能，并提供更多的选择性治疗。我们的初步研究已经确定了一种受体，它在斑块新生血管上高表达，但在内皮或正常动脉上不表达。我们将使用我们的合作者优化过的受体特异性靶向多肽来验证配体导向的纳米颗粒在体内对糖尿病斑块新生血管的作用。我们还将使用一种新的糖尿病诱导斑块血管生成的动物模型和噬菌体展示方法来筛选和鉴定糖尿病斑块新生血管的血管可及、高亲和力配体/受体伙伴。这项探索性研究的结果将加强我们对血管斑块及其在动脉粥样硬化和血管并发症进展中的作用的分子理解。我们的筛查应该确定其他斑块新生血管结合候选者，并将改进斑块血管生成依赖靶向的体内验证方法，这将推动未来诊断和治疗靶向试剂的发展，以减少患有或不患有糖尿病的患者的大血管并发症。

DESCRIPTION (provided by applicant): Networks of small caliber blood vessels, termed vasa vasorum, are confined to the outer media and adventitia layers of major large caliber blood vessels; however, these vessels proliferate and invade the intima during atherosclerosis and other conditions of vasculitis. Increasing data suggests that the permeability, inflammatory cell recruitment and bleeding properties of plaque neovascularization promote atherosclerosis and its complications. The neovascular network invading atherosclerotic lesions may also serve as a more efficient portal for drug penetration into diseased arteries to control their occlusion and plaque instability. In diabetes, we have recently shown the tendency for plaques to acquire neovascularization is significantly increased and accelerates atherosclerosis. Thus, the characterization of molecules displayed on plaque neovascularization in diabetes can identify important ligand/receptor interactions that take place on this unique microvascular endothelium and mediate pathologic functions. These molecular targets can be exploited to deliver molecular imaging agents or drugs to the pathologic neovascularization and minimize their effects on normal arteries. We hypothesize angiogenic plaque capillaries display unique molecules that promote atherosclerosis in diabetes, which will useful to understand and modify its functions and to deliver more selective treatments. Our preliminary studies have identified a receptor that is highly expressed on plaque neovascularization, but not on the endothelium or normal arteries. We will use receptor-specific targeting peptides that have been optimized by our collaborators to validate ligand-directed nanoparticle delivery to diabetic plaque neovascularization in vivo. We will also use a novel animal model of diabetes-induced plaque angiogenesis and phage display methods to screen and identify a repertoire of vascular- accessible, high affinity ligand/receptor partners on plaque neovascularization in diabetes. Results from this exploratory study will enhance our molecular understanding of plaque vasa vasorum and its role in progression of atherosclerosis and vascular complications. Our screen should identify other plaque neovascularization binding candidates and will refine methods for in vivo validation of plaque angiogenesis-dependent targeting that will drive future development of targeting agents for diagnostics and treatments to reduce macrovascular complications in patients with or without diabetes.