Molecular Targeting of Plaque Angiogenesis in Diabetes

糖尿病斑块血管生成的分子靶向

基本信息

批准号：
8097905
负责人：
KAREN Simpson MOULTON
金额：
$ 22.59万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8097905
关键词：
Acceleration Adverse drug effect Affinity Angiogenesis Inhibitors Animal Model Area Arterial Fatty Streak Arteries Atherosclerosis Binding Blood Vessels Blood capillaries Blood flow Caliber Cell Adhesion Molecules Cell Proliferation Cells Collaborations Colorado Data Development Diabetes Mellitus Diabetic Retinopathy Diabetic macrovascular disease Diagnostic Drug Delivery Systems Dyslipidemias Endothelium Functional disorder Future Goals Growth Hemorrhage Heterogeneity High Prevalence Homing Hyperglycemia Hyperplasia Hypertension Image Immune Individual Inflammatory Injury Insulin-Dependent Diabetes Mellitus Integrins Invaded Knowledge Ligands Lung Malignant Neoplasms Mediating Methods Mining Modeling Molecular Molecular Target Monitor Myocardial Infarction Pathologic Pathologic Neovascularization Patients Penetration Peptides Permeability Phage Display Pharmaceutical Preparations Plasma Cells Proliferating Property Proteinuria Receptor Activation Retinal Diseases Role Rupture Schools Seminal Sirolimus Stroke Technology Testing Thrombosis Tissues Tunica Adventitia Validation Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Vascular Permeabilities Vasculitis abstracting angiogenesis capillary cost diabetic high risk in vivo macrovascular disease molecular imaging nanoparticle neovascular neovascularization non-diabetic novel receptor targeted delivery treatment response vasa vasorum vascular bed

项目摘要

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. PUBLIC HEALTH RELEVANCE: The goals of this project will demonstrate a more precise means to deliver drugs or imaging agents to unique areas of abnormal blood vessel growth that contribute to vascular complications and cause heart attacks and strokes, particularly for patients with diabetes. Results may reduce costs and side effects of drugs by concentrating drugs in the tissues where they are most needed.

描述（由申请人提供）：小口径血管的网络（称为Vasa vasorum）仅限于大型大能力血管的外媒体和外膜层；但是，这些血管在动脉粥样硬化和其他血管炎状态期间扩散并侵入内膜。越来越多的数据表明，斑块新生血管形成的渗透性，炎症细胞募集和出血特性会促进动脉粥样硬化及其并发症。入侵动脉粥样硬化病变的新生血管网络也可能是药物渗透到患病动脉中的更有效的门户，以控制其闭塞和斑块不稳定。在糖尿病中，我们最近表明，斑块获得新血管形成的趋势显着增加并加速了动脉粥样硬化。因此，在糖尿病中斑块新血管形成上显示的分子的表征可以鉴定出在这种独特的微血管内皮上发生的重要配体/受体相互作用并介导病理功能。可以利用这些分子靶标将分子成像剂或药物递送到病理新生血管形成，并最大程度地减少其对正常动脉的影响。我们假设血管生成斑块毛细血管显示出独特的分子，可促进糖尿病的动脉粥样硬化，这将有助于理解和修改其功能并提供更多选择性的治疗方法。我们的初步研究已经确定了一种受体，该受体在牙菌斑的新血管形成上高度表达，但不能在内皮或正常动脉上表达。我们将使用我们的合作者优化的受体特异性靶向肽来验证体内配体指导的纳米颗粒递送到体内糖尿病斑块新生血管形成。我们还将使用糖尿病诱导的斑块血管生成和噬菌体显示方法的新型动物模型来筛查和鉴定糖尿病中斑块新生血管化的血管可及的高亲和力配体/受体伴侣的曲目。这项探索性研究的结果将增强我们对斑块瓦萨（Vasa vasorum）的分子理解及其在动脉粥样硬化和血管并发症进展中的作用。我们的屏幕应确定其他斑块新血管结合候选者，并将完善用于体内验证牙菌血管生成依赖性靶向靶向的方法，这些方法将推动未来的诊断和治疗靶向药物的开发，以减少患有或没有糖尿病患者的大型血管并发症。公共卫生相关性：该项目的目标将证明一种更精确的手段，将药物或成像剂传递到异常血管生长的独特领域，这会导致血管并发症，并引起心脏病发作和中风，尤其是对糖尿病患者。结果可以通过将药物浓缩在最需要的组织中，从而降低药物的成本和副作用。