Mechanisms of retinal vascular development

血管是胚胎中最早发育的器官之一，对组织功能和体内平衡至关重要。出生后，动脉和静脉被认为是终末分化的，但它们保留了足够的可塑性来形成新的血管。 这个NSERC计划是建立在该领域最近的一个重大突破之上的：我们在小鼠视网膜中发现了衰老细胞（过早衰老）产生一系列有助于血管再生的因子。我们的初步数据还显示了胎儿暂时性血管（发育中的眼睛称为玻璃体）的过早衰老特征，这些血管在出生后将退化，被最终的视网膜血管所取代。有趣的是，这些动脉起源的衰老玻璃体是动态的，可以失去其原始身份，并获得静脉身份。发育性衰老如何参与血管眼发育过程中的动静脉身份转换仍然没有答案。 我的长期目标是破译在发育中的眼睛中启动和调节衰老的细胞和分子机制，并确定这一过程如何影响内皮细胞（EC）的可塑性，这是在稳态条件下血管生长所需的。基于坚实的初步数据（已发表和尚未发表），这项工作将测试的一般假设，在胎儿玻璃体血管的衰老不仅是需要他们的回归，而且为随后的生长确定的视网膜血管。在接下来的五年里，我的研究计划将围绕以下短期目标：1。鉴定玻璃体和视网膜EC亚群及其调节机制。（短期目标）2。确定动静脉规格是否需要发育衰老。（短期和中期目标）3。确定玻璃体细胞的衰老分布及其在动静脉特化中的作用。（今后的工作）。结论：这个多学科的计划将揭示一个新的方面的生物功能的非常规有益的衰老。视觉领域的研究实验室专注于研究视网膜中最丰富的细胞（光感受器，神经元和免疫细胞）。然而，有大量的证据表明血管成分在眼睛的功能中起着重要作用。为了弥合这一知识差距，我的研究计划将破译负责控制胚胎和成人视网膜血管中血管细胞身份和功能的细胞和分子机制。我们希望成为研究非常规发育衰老在眼血管可塑性中的作用的先驱，其特征在于动静脉特异性。NSERC的这项研究计划将为血管形成带来一种全新的思维方式，并有望比以前认为的更广泛，并为在其他血管化组织中研究此类机制铺平道路。

BACKGROUND Blood vessels are among the first organs to develop in the embryo and are critical for tissue function and homeostasis. Postnatally, arteries and veins are considered terminally differentiated, but they retain enough plasticity to form new blood vessels. This NSERC program is built on a recent major breakthrough in the field: We discovered in the mouse retina, senescent cells (that age prematurely) producing a series of factors that contribute to vascular regrowth. Our preliminary data, also showed features of premature senescence in fetal transitory vessels, called hyaloids in developing eyes, that will regress after birth to be replaced by definitive retinal blood vessels. Interestingly, these senescent hyaloids of arterial origin are dynamic and can lose their original identity and acquire a vein identity. How developmental senescence partakes in arteriovenous identity switch during vascular eye development remains unanswered. My LONG-TERM GOAL is to decipher the cellular and molecular mechanisms that initiate and regulate senescence in the developing eye, and determine how this process influences endothelial cell (EC) plasticity as needed for vascular growth in homeostatic conditions. Based on solid preliminary data (published and not yet published), this work will test the general hypothesis that senescence in fetal hyaloid vessels is needed not only for their regression but also for the subsequent growth of definitive retinal vessels. For the next five years, my research program will revolve around the following SHORT-MID TERM GOALS: 1. Identify hyaloid and retinal EC sub-populations and the mechanisms regulating their identity. (Short-term goal) 2. Determine whether developmental senescence is required for arteriovenous specification. (Short and mid-term goal) 3. Determine cellular senescence distribution in hyaloid cells and its role in arteriovenous specification. (Future work). CONCLUSION: This multidisciplinary program will reveal a new facet of the biological functions of unconventional beneficial senescence. Research laboratories in the vision field focus on studying the most abundant cells in the retina (photoreceptors, neurons and immune cells). Yet, there is a wealth of evidence pointing to a significant role of the vascular component in the functioning of the eye. To bridge this gap of knowledge, my research program will decipher the cellular and molecular mechanisms responsible for the control of vascular cell identity and function in embryonic and adult retinal vessels. We expect to be pioneers in investigating the role of unconventional developmental senescence in eye blood vessels plasticity, characterized by arteriovenous specification. This NSERC research program will bring an entirely new way of thinking about blood vessel formation and holds a lot of promises to be more widespread than previously thought and could pave the way to study such mechanisms in other vascularized tissues.