HYPOXIC REGULATION OF VASCULAR GROWTH IN VITRO

描述：（候选人的摘要）这个医生科学家奖 应用重点是体外实验系统的开发 探讨缺氧在眼血管调节中的作用 增长 新血管的形成，或血管生成，对于 伤口愈合，周期性子宫内膜增生，胎盘成熟 在成熟组织中，血管内皮细胞 以分化的静止状态存在，很少增殖。 它 这种静止状态很可能至少部分地由以下因素维持： 局部抑制和刺激因子之间的平衡。异常 眼内血管增生是视觉系统的最接近事件， 早产儿视网膜病变，增殖性糖尿病视网膜病变， 新生血管性青光眼、年龄相关性黄斑变性和视网膜静脉 闭塞 视网膜缺血会增加随后发生眼部缺血的风险。 新血管形成和本提案中描述的研究检查了 缺氧改变了抑制性和 血液中内皮细胞增殖的刺激介质 血管壁 转化生长因子-B（TGF-B）已被证明 抑制培养的内皮细胞的增殖。 的影响 然而，缺氧对TGF-B产生的影响尚不清楚。 研究 将检查缺氧在调节中的作用， 转化生长因子B 我们的假设预测， 抗血管生成因子如TGF-β在缺氧条件下 导致内皮细胞生长抑制作用的丧失， 随后的新血管形成。 血管内皮生长因子 是一种有效的内皮细胞有丝分裂原， 在缺氧条件下上调。 组织缺氧一直是 假设作为一个刺激释放的扩散 血管生成因子。 VEGF是这方面的主要候选者 作用研究将检查VEGF对内皮细胞的作用， 在低氧条件下增殖。 第二个假设是 测试的是VEGF的基因表达受缺氧调节。 是 已知VEGF和VEGFmRNA的量在以下条件下增加： 低氧条件下。 然而，发生这种情况的机制是 未知。实验将检查增加的相对作用 VEGF mRNA的转录和半衰期延长的可能性 此外，VEGF mRNA的低氧反应元件 负责VEGF缺氧诱导的DNA将被表征。 本提案中概述的研究将审查各种机制， 缺氧会导致眼部血管生成，这将增加我们的理解 我们的最终目标是 更接近于治疗这些致盲疾病。 有机会开展本提案中概述的研究， 接受正规的细胞和分子生物学培训将提供 向申请人提供下一步所需的培训机会 作为一名独立的医生， 科学家

DESCRIPTION: (Candidate's Abstract) This Physician Scientist Award application focuses on the development of in vitro experimental systems to examine the role of hypoxia in the regulation of ocular vascular growth. New blood vessel formation, or angiogenesis, is important in wound healing, cyclic endometrial proliferation, placental maturation and in normal development.In mature tissues, vascular endothelial cells exist in a differentiated, quiescent state and rarely proliferate. It is likely that this quiescent state is maintained, at least in part, by a balance between local inhibitory and stimulatory factors.Abnormal blood vessel proliferation in the eye is the proximate event in visual loss in retinopathy of prematurity, proliferative diabetic retinopathy, neovascular glaucoma, age-related macular degeneration and retinal vein occlusion. Retinal ischemia increases the risk of subsequent ocular neovascularization and the studies described in this proposal examine the hypothesis that hypoxia alters the balance between inhibitory and stimulatory mediators of endothelial cell proliferation in the blood vessel wall. Transforming growth factor-B (TGF-B) has been shown to inhibit the proliferation of endothelial cells in culture. The effects of hypoxia on the production of TGF-B, however, are unknown. Studies to be performed will examine the role of hypoxia in the regulation of TGF-B. Our hypothesis predicts that there will be a relative decrease in antiangiogenic factors such as TGF-B under conditions of hypoxia leading to the loss of inhibition of endothelial cell growth and subsequent neovascularization. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and has been demonstrated to be upregulated under conditions of hypoxia. Tissue hypoxia has been postulated to act as a stimulus for the release of a diffusible angiogenic factor from the retina. VEGF is a prime candidate for this role. Studies will examine the effects of VEGF on endothelial cell proliferation under hypoxic conditions. The second hypothesis to be tested is that gene expression of VEGF is regulated by hypoxia. It is known that both the amount of VEGF and VEGF mRNA are increased under hypoxic conditions. The mechanism(s) by which this occurs, however, is unknown.Experiments will examine the relative roles of increased transcription of VEGF mRNA and the possibility of an increased half-life of the VEGF mRNA.In addition, the hypoxic response element of the VEGF DNA responsible for the hypoxic induction of VEGF will be characterized. The studies outlined in this proposal will examine mechanisms by which hypoxia leads to ocular angiogenesis and will add to our understanding of ocular neovascularization with the ultimate goal of bringing us closer to a treatment of these blinding diseases. The opportunity to carry out the studies outlined in this proposal and receive formal training in cellular and molecular biology will afford the applicant the training opportunity that is required as the next step toward the establishment of her career as an independent physician scientist.