In-Stent Stenosis Model in Type 2 Diabetic Rats

2 型糖尿病大鼠支架内狭窄模型

• 批准号: 6833587
• 负责人: Tiangen Wu
• 金额: $ 24.21万
• 依托单位: BIOMEDICAL RESEARCH MODELS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6833587
• 关键词: artery stenosis; biomarker; biomaterial development /preparation; biomaterial evaluation; blood vessel prosthesis; carotid artery; diabetic angiopathy; disease /disorder model; histopathology; laboratory rat; model design /development; noninsulin dependent diabetes mellitus; proteomics; restenosis

DESCRIPTION (provided by applicant): Coronary artery disease affects 12 million Americans and is the number on killer in the United States. Diabetes affects over 16 million Americans, with more than 80,000 new cases diagnosed each year. Cardiovascular complications of diabetes kills 75% of diabetics. Routine clinical management for coronary artery disease involves percutanesous transluminal coronary angioplasty (PTCA) and coronary artery stenting (CAS). Re-narrowing of an opened coronary artery (restenosis) occurs in approximately 50% of patients within six months of PTCA and in 35% of patients following CAS and requires intervention. Currently, a bottleneck exists in pre-clinical testing arena for new technology and therapeutics due to limits of current animal models that threatens to handicap R&D efforts. Hence, the major long-term objective of this proposal is to develop and validate a novel in-stent stenosis animal model system to accelerate advances in CAD therapeutics and device testing. This patented technology will combine advances in stent design and scale with a well-characterized model of Type2 diabetes and offer via licensing agreement, a potential powerful system to also study vascular restenosis. Biomedical Research Models, Inc. requests SBIR Phase I funding to test the feasibility of a new stent design rat model system to study in-stent stenosis. Specific Aim 1 will involve the manufacture of BRM ministents and deliver devises (balloon catheter) according to specifications. The mini-stent will then be fatigue-tested according to industry standards. Also, Specific Aim 1 will compare the BRM mini-stent and balloon catheter relative to commercial stent in normal BBZDR lean rats for a period of 8 weeks. Stents will be deployed in the left common carotid artery of two cohorts of twelve rats each. Animal health will be monitored and gross pathology will be recorded at necropsy. In-stent and uninjured segments of carotid arteries will be fixed, resin-embedded and sectioned for histopathology, post mortem. Differences in stent integrity, vessel injury, and in stent stenosis will be reported. Success will be judged relative to pathology and stenosis reported. In Specific Aim 2, the BRM mini-stent will be tested in the BBZDR/Wor rat, a well -characterized model of Type 2 diabetes. A cohort of 12 obese diabetic (4 months duration) will be compared to an age-matched cohort of lean non-diabetic BBZDR/Wor rats. Similar endpoint analyses will be performed as described in Specific Aim 2. In Phase II, data collected using this animal model system will be used to identify novel biomarkers of stenosis and further explore this model system as drug delivery platform to screen potential novel therapies for CAD.

描述（由申请人提供）： 冠状动脉疾病影响了1200万美国人，是美国杀手的人数。糖尿病会影响超过1600万美国人，每年诊断出80,000例新病例。糖尿病的心血管并发症会杀死75％的糖尿病患者。冠状动脉疾病的常规临床治疗涉及经文透明冠状动脉血管成形术（PTCA）和冠状动脉支架（CAS）。在PTCA的六个月内，大约50％的患者和35％的患者在CAS之后的患者中重新纳入开放的冠状动脉（再狭窄）发生，需要干预。目前，由于当前动物模型的限制威胁到残障研发工作，因此在临床前测试领域中存在瓶颈。因此，该提案的主要长期目标是开发和验证一种新型的狭窄动物模型系统，以加速CAD疗法和设备测试的进步。这项获得专利的技术将结合支架设计和规模的进步与Type2糖尿病的特色模型，并通过许可协议提供，这是一种潜在的强大系统，可以研究血管再狭窄。生物医学研究模型，Inc。要求SBIR I期资金来测试新的支架设计大鼠模型系统以研究内部狭窄的可行性。特定的目标1将涉及BRM碎屑的制造，并根据规格提供设计（气球导管）。然后，将根据行业标准对小型固定型进行疲劳测试。此外，特定的目标1将比较BRM迷你结构导管和气球导管相对于正常BBZDR瘦大鼠的商业支架，为期8周。支架将部署在两只十二只大鼠的左颈动脉中。动物健康将受到监测，并将记录在尸检中。将颈动脉动脉的内部和未污染片段固定，树脂装饰并切开以进行组织病理学，验尸后。支架完整性，血管损伤和支架狭窄的差异将报道。相对于病理学和狭窄报告，将判断成功。在特定的目标2中，将在BBZDR/WOR大鼠中测试BRM迷你结构，这是2型糖尿病的特征型模型。将12个肥胖的糖尿病患者（持续4个月）组成的队列与年龄匹配的非糖尿病BBZDR/WOR大鼠的队列进行比较。将如特定目标2所述进行类似的终点分析。在第二阶段，使用该动物模型系统收集的数据将用于识别狭窄的新生物标志物，并进一步探索该模型系统作为筛选CAD潜在新型疗法的药物输送平台。