Genetic Determinants of Collateral Wall Specialization and Ischemic Remodeling

描述（由申请人提供）：本申请描述了一个为期4年的培训计划，促进学术研究事业的发展。主要研究者即将完成他在北卡罗来纳州大学的博士后培训阶段，现在需要通过一个简短的指导阶段来扩大他的科学技能，然后才能作为缺血侧支重塑领域的独立研究者。 拟议的研究将集中在正常静息和缺血条件下预先存在的侧枝的生物学。这个提议的研究与导师的研究相关但不同。Faber实验室最近的工作比较了两种小鼠品系，我们观察到它们在侧支密度、重塑能力和VEGF-A表达方面存在明显差异。这种小鼠品系依赖性差异建立了C57 BL/6和BALB/c品系作为研究缺血侧支重塑决定因素的优良模型。本申请中提出的实验将使用细胞、分子和免疫组织化学技术的分类来研究侧支壁细胞的生物学、基因表达谱和调节侧支在缺血动物模型中重塑的能力的遗传决定因素。具体目标包括：1）测量侧支血流的基本性质并确定侧支内皮细胞取向是否是随机的并与侧支重塑期间的曲折模式相关，2）鉴定保护侧支免于表达炎症样和促血栓形成表型并保护侧支免于在扰动、缓慢和振荡流动环境中血管退化的潜在遗传机制，和3）使用两种遗传上不同的小鼠品系C57 BL/6和BALB/c研究缺血时侧支重塑能力的变化的基础。 该提案将提供侧支内皮细胞的第一个形态学和遗传学分析，并开始定义侧支如何在扰动、缓慢和振荡的流动环境下免受炎症、血栓形成和血管退化的影响。此外，这项建议的发现将提供深入了解侧枝扩大能力变化的遗传基础。这项研究的目的是获得新的和重要的知识，可以鼓励新的策略，以提高缺血性血管疾病患者侧支血管的生长和稳定性。

DESCRIPTION (provided by applicant): This application describes a 4 year training program that fosters the development of a career in academic research. The principal investigator is near completion of his post-doctoral training phase at the University of North Carolina and now requires broadening of his scientific skills with a brief mentoring phase before seeking independence as an investigator in the field of collateral remodeling in ischemia. The proposed research will focus on the biology of pre-existing collaterals under normal resting and ischemic conditions. This proposed research is related but divergent from the mentor's research. Recent work in the Faber laboratory compared two mouse strains that we observed have stark differences in collateral density, capacity to remodel and VEGF-A expression. This mouse strain-dependent difference establishes the C57BL/6 and BALB/c strains as excellent models for studying the determinants of collateral remodeling in ischemia. Proposed experiments in this application will use an assortment of cellular, molecular, and immunohistochemical techniques to study the biology of collateral wall cells, gene expression profiles and the genetic determinants that regulate the capacity of collaterals to remodel in an animal model of ischemia. Specific aims include: 1) Measure fundamental properties of collateral blood flow and determine if collateral endothelial cell orientation is stochastic and correlates with the tortuous pattern during collateral remodeling, 2) Identify the underlying genetic mechanisms that protect collaterals from expressing an inflammation-like and pro-thrombotic phenotype and that protect collaterals from vascular regression in a disturbed, slow and oscillatory flow environment, and 3) Investigate the basis for variation in the capacity of collaterals to remodel in ischemia using two genetically distinct mouse strains, the C57BL/6 and BALB/c. This proposal will provide the first morphologic and genetic analyses of collateral endothelial cells and begin to define how collaterals are protected from inflammation, thrombosis and vascular regression under a disturbed, slow and oscillatory flow environment. In addition, findings from this proposal will provide insight into the genetic basis for variation in capacity of collaterals to enlarge. The goal of the proposed research is to acquire new and important knowledge that may encourage new strategies to enhance the growth and stability of collateral vessels in patients with ischemic vascular disease.