Vessel Maturation as a Regulator of Tissue Remodeling

描述(由申请人提供)： 我的长期职业目标是为血管生成研究的进步做出贡献。作为一名研究人员和心脏病专家，我的原则是致力于研究。我早期的研究表明，脂肪组织的生长依赖于血管生成。目前的研究方向是检查血管成熟度作为组织重塑的调节因素。这些发现对血管内皮细胞对组织生长的调控具有重要意义。K02奖将使我能够将75%以上的精力投入到实验室，使其免受非研究义务的保护。这不仅会加深我的学习，也会极大地促进我作为一名调查人员的发展。 血管重塑和成熟是血管生成后的关键事件。血管密度是微调的，而新生的管子还不成熟。在大多数组织中，这种血管可塑性是暂时的。然后，周细胞稳定结构，形成成熟、静止的血管系统。相比之下，肿瘤血管保持不成熟。这使得可以继续重建，但也使肿瘤血管对抗血管生成药物敏感。 我们认为，脂肪组织和肿瘤一样，维持着一种长期不成熟的血管系统。与大多数成人器官不同，脂肪组织可以经历快速、实质性的质量转移。我们先前的工作表明，脂肪血管系统也是可塑性的，对血管生成抑制剂很敏感。我们的假设是，脂肪组织的血管系统是慢性不成熟的，因此在发育后保持其可塑性。我们将在各种体重调整条件下检测野生型和遗传性肥胖小鼠脂肪组织重塑过程中血管成熟度的标志物。我们将表征和研究血管生成素/TiE系统和周细胞含量的功能意义。将脂肪瘤与正常人体脂肪组织进行比较，在血管成熟程度更大、病理更稳定。这些研究有望进一步加深我们对血管重塑机制的理解，并确定通过血管系统调节组织生长的潜在策略。

DESCRIPTION (provided by applicant): My long-term career goal is to contribute to the advancement of angiogenesis research. As an investigator and cardiologist, my principle commitment is to research. My earlier studies showed adipose tissue growth was angiogenesis dependent. Current efforts are directed at examining vascular maturation as a regulator of this tissue remodeling. These findings have implications for endothelial regulation of tissue growth. A K02 award would enable me to devote greater than 75% effort to the laboratory protected from non-research obligations. This would not only further the studies but also greatly advance my development as an investigator. Vessel remodeling and maturation are critical events following angiogenesis. Vascular density is fine-tuned while the nascent tubes are still immature. In most tissues this vascular plasticity is transient. Pericytes then stabilize the structure and a mature, quiescent vasculature results. In contrast, tumor vessels stay immature. This enables continued remodeling but also renders the tumor vasculature susceptible to anti-angiogenic drugs. We propose that adipose tissue, like tumors, maintains a chronically immature vasculature. Unlike most adult organs, adipose tissue can undergo rapid, substantial shifts in mass. Our prior work shows that adipose vasculature is also plastic and is susceptible to angiogenesis inhibitors. Our hypothesis is that adipose tissue vasculature is chronically immature, thereby preserving its plasticity after development. We will examine markers of vessel maturity during adipose tissue remodeling in wildtype and genetically obese mice under a variety of weight modifying conditions. We will characterize and examine the functional significance of the angiopoietin/tie system and pericytes content. Lipomas and normal human adipose tissue will be compared in terms of vascular maturation was greater in the more stable pathology. These studies are expected to further our understanding of the mechanisms of vascular remodeling and identify potential strategies for regulating tissue growth via the vasculature.