Cellular and molecular mechanisms of human choroidal and retinal vascularisation

新生血管的异常生长是所有年龄段的人失明的主要原因。在早产儿中，视网膜血管的变化导致早产儿视网膜病变(ROP)，是世界上导致婴儿失明的主要原因。在患有老年性黄斑变性(ARMD)的老年人中，脉络膜中的血管可以生长到视网膜内和视网膜下，从而导致灾难性的视力丧失。这种异常的血管生长与最常见的致盲原因之间的联系促使人们寻求更好地了解眼睛中的血管生长是如何在健康组织中受到控制的，以及这些控制在疾病中是如何失败的。我们的建议直接解决了这个问题。最近的研究表明，这种新生血管不仅是对诱导血管生成的分子局部浓度上升的反应，而且还需要抑制血管生成的内源性分子水平的下降。我们的研究将研究新发现的血管生成生长因子(VEGFs)及其受体以及血管生成抑制物(VEGI和PEDF)在发育中和成人视网膜和脉络膜中的表达。我们将研究人类脉络膜形成的机制。我们的初步结果表明，血管生成(通过转化血管前体细胞形成血管)在人类视网膜和脉络膜的形成中发挥着重要作用。此外，这些令人兴奋的结果表明，以前不知道在这些过程中发挥作用的新的生长刺激因子和抑制因子参与其中。我们的研究将导致对驱动这一过程的血管生长因子和抑制剂的新见解，从而为ARMD的治疗提供新的治疗靶点。澳大利亚人口的迅速老龄化以及随之而来的ARMD发病率预计在未来20年翻一番，表明了我们研究的紧迫性。

The abnormal growth of new blood vessels is a major cause of blindness in people of all ages. In premature infants, changes in retinal blood vessels results in Retinopathy of Prematurity (ROP) the leading cause of infant blindness in the world. In older adults with age-related macular degeneration (ARMD), vessels in the choroid can grow into and under the retina where they can cause catastrophic loss of vision. This association of abnormal vessel growth with the most common causes of blindness has motivated the search for a better understanding of how blood vessel growth in the eye is controlled in healthy tissues and how these controls fail in disease. Our proposal addresses this issue directly. Recent work shows that this neovascularization is not only a response to a rise in the local concentration of molecules that induce such angiogenesis, but also requires a fall in the levels of endogenous molecules that inhibit angiogenesis. Our study will investigate the expression of newly identified angiogenic growth factors (VEGFs) and their receptors as well as angiogenic inhibitors (VEGI and PEDF) in the developing and adult human retina and choroid. We will examine the mechanisms by which the human choroid is formed. Our preliminary results suggests the novel insight that vasculogenesis (the formation of blood vessels via transformation of vascular precursor cells) plays a major role the formation of both the human retina and choroid. Further, these exciting results suggest involvement of novel growth stimulators and inhibitors previously not known to play a role in these processes. Our studies will lead to new insights regarding the vascular growth factors and inhibitors that drive this process, thus leading to a rational basis for new therapeutic targets for the treatment of ARMD. The rapid aging of the Australian population and the consequent predicted doubling of ARMD incidence in the next 20 years demonstrates the urgency of our studies.