Mechanisms of retinal vascular development

视网膜血管发育机制

• 批准号: RGPIN-2020-06230
• 负责人: Oubaha, Malika
• 金额: $ 2.19万
• 依托单位: Université du Québec à Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=741103
• 关键词: Mechanisms; retinal; vascular; development

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.

背景血管是胚胎中最早发育的器官之一，对组织功能和动态平衡至关重要。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项目建立在该领域最近的一项重大突破的基础上：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过早衰老的特征，在发育中的眼睛被称为玻璃体，出生后会退化，被确定的视网膜血管所取代。有趣的是，这些源于动脉的老化的玻璃体是动态的，可能会失去它们原来的身份，而获得静脉身份。在血管眼发育过程中，发育衰老是如何参与动静脉同一性转换的，目前还没有答案。我的长期目标是破译启动和调节发育中眼睛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，这是血管在动态平衡条件下生长所必需的。基于可靠的初步数据(已发表和尚未发表)，这项工作将检验这一普遍假设，即胎儿玻璃体血管的衰老不仅是其退化所必需的，而且对随后明确的视网膜血管的生长也是必要的。在接下来的五年里，我的研究计划将围绕以下中短期目标：1.确定玻璃体和视网膜EC亚群及其调节身份的机制。(短期目标)2.确定动静脉规范是否需要发育衰老。(短期和中期目标)3.确定玻璃样细胞中细胞衰老的分布及其在动静脉规范中的作用。(未来工作)。结论：这一多学科计划将揭示非常规有益衰老生物学功能的一个新方面。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，有大量证据表明，血管成分在眼睛的功能中发挥着重要作用。为了弥合这一知识鸿沟，我的研究计划将破译负责控制胚胎和成年视网膜血管中血管细胞身份和功能的细胞和分子机制。我们期望成为研究非常规发育衰老在以动静脉规范为特征的眼血管可塑性中的作用的先驱。NSERC的这一研究计划将带来一种全新的血管形成思维方式，并有望比之前想象的更广泛，并可能为在其他血管组织中研究此类机制铺平道路。