Molecular Targeting of Plaque Angiogenesis in Diabetes

描述（由申请人提供）：小口径血管网络，称为血管管，局限于主要大口径血管的外中膜和外膜层；然而，在动脉粥样硬化和其他血管炎的情况下，这些血管增殖并侵入内膜。越来越多的数据表明，斑块新生血管的渗透性、炎症细胞募集和出血特性促进了动脉粥样硬化及其并发症。侵入动脉粥样硬化病变的新血管网络也可以作为药物渗透病变动脉以控制其闭塞和斑块不稳定的更有效门户。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，表征糖尿病斑块新生血管中显示的分子可以识别发生在这种独特的微血管内皮上的重要配体/受体相互作用并介导病理功能。这些分子靶点可用于向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。我们假设血管生成斑块毛细血管显示促进糖尿病动脉粥样硬化的独特分子，这将有助于理解和修改其功能，并提供更多选择性治疗。我们的初步研究已经确定了一种受体，它在斑块新生血管中高度表达，但在内皮细胞或正常动脉中却不表达。我们将使用由我们的合作者优化的受体特异性靶向肽来验证配体定向纳米颗粒递送到糖尿病斑块新生血管的体内。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中血管可及的高亲和力配体/受体伙伴。这项探索性研究的结果将增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。我们的筛选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药物的发展，以减少糖尿病患者或非糖尿病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.