HYPOXIC REGULATION OF VASCULAR GROWTH IN VITRO

描述：(候选人摘要)本届医师科学家奖 应用重点是体外实验系统的开发 探讨低氧在眼血管调节中的作用 成长。新的血管形成，或血管生成，在 伤口愈合、子宫内膜周期性增殖、胎盘成熟 在正常发育中。在成熟组织中，血管内皮细胞 以分化、静止的状态存在，很少增殖。它 这种静止状态可能至少部分地通过以下方式维持 局部抑制因素和刺激因素之间的平衡。异常 眼内血管的增殖是视力的最近的事件 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、老年性黄斑变性和视网膜静脉 遮挡。视网膜缺血增加继发性眼病的风险 新生血管和这项建议中描述的研究检查 低氧改变抑制和抑制之间的平衡的假说 血液中内皮细胞增殖的刺激介质 血管壁。转化生长因子-B(转化生长因子-B)已被证明 抑制培养中内皮细胞的增殖。其影响 然而，低氧对转化生长因子-β产生的影响尚不清楚。研究 将进行的研究将检查低氧在调节 转化生长因子-B我们的假设预测会有一个相对的减少 缺氧条件下转化生长因子-β等抗血管生成因子的变化 导致内皮细胞生长抑制的丧失和 随后的新生血管。血管内皮生长因子 是一种有效的内皮细胞有丝分裂原，已被证明是 在低氧条件下上调。组织缺氧一直是 作为一种刺激释放一种可扩散的 视网膜中的血管生成因子。血管内皮生长因子是这方面的主要候选者。 角色。研究将检测血管内皮生长因子对内皮细胞的影响 在低氧条件下增殖。第二个假设是 实验证明，低氧对血管内皮细胞生长因子的基因表达有调节作用。它是 已知血管内皮细胞生长因子和血管内皮细胞生长因子信使核糖核酸在 低氧状态。然而，发生这种情况的机制(S)是 未知。实验将检验增加的相对作用 血管内皮生长因子基因转录与半衰期延长的可能性 此外，血管内皮细胞生长因子的缺氧反应元件 负责低氧诱导血管内皮细胞生长因子的DNA将被描述。 本提案中概述的研究将审查通过哪些机制 低氧会导致眼部血管生成，这将加深我们的理解 眼睛新生血管的最终目标是给我们带来 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， 接受细胞和分子生物学的正式培训将负担得起 申请者下一步所需的培训机会 她作为一名独立医生的职业生涯的建立 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.