课题基金 / 基金详情

Innate Immunomodulation of Retinal Vascular Development

Innate Immunomodulation of Retinal Vascular Development
视网膜血管发育的先天免疫调节
批准号:
10924832
负责人:
Gopalan Gnanaguru
金额:
$44.5万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-06-01 至 2025-09-29

项目摘要

项目成果

Gopalan Gnanaguru的其他基金

相似基金

相关文献

中文摘要
翻译
项目摘要 视网膜血管形成是一个高度调控的过程,需要多细胞串扰和 互动。由于视网膜血管发育的复杂性,存在着几个关键的知识空白 这一点需要得到解决。例如,调节视网膜血管发育的关键胶质细胞类型是 星形胶质细胞,它为血管形成奠定了模板。内皮细胞在空间上迁移 组织星形细胞模板以形成浅血管,该浅血管产生三个相互连接的血管 在成熟的视网膜中的几层。星形胶质细胞发育或丧失过程中星形细胞模板的破坏 成年后与血管的关系可能不利于血管的生长、完整性和功能。这个 潜在的细胞和分子信号机制,调节星形胶质细胞的空间图案和 发育过程中随后的有组织的血管形成仍然不完全清楚。澄清 控制血管发育和功能的分子机制是必要的,以确定更多 针对致盲视网膜血管病变的有针对性的治疗策略,并确定哪些关键的 在某些情况下,发育过程不应成为目标,例如早产儿视网膜病变。我们的 主要目的是描述调控星形胶质细胞模板空间排列的信号机制和 血管网络的形成。 我们的初步发现有力地支持了本研究的基本原理。我们的rna-seq数据显示 在视网膜血管发育过程中,特异性趋化因子和补体基因表达水平升高。 有趣的是,一个受影响的趋化因子受体的缺失会扰乱星形胶质细胞模板的形成和 小胶质细胞的募集和分布。另一方面,删除补体成分会导致 异常致密的星形细胞模板和畸形的过度尖端细胞形成。基于这些小说 结果,我们假设小胶质细胞趋化因子信号和补体激活对正常至关重要。 视网膜血管发育。我们将在以下两个具体目标中反驳或验证我们的假设:AIM 1:确定趋化因子信号是否招募小胶质细胞来调节星形胶质细胞模板组装。目标2:实现 明确补体受体在星形胶质细胞模板和血管网络形成中的作用。我们将利用 创新的基于多重RNA/蛋白质的分析,新的体外迁移分析,独特的报告小鼠,以及 Cre/lox动物的细胞特异性缺失。我们期望建议的研究能顺利完成。 识别先天性免疫系统在调节高度复杂的视网膜血管发育中的新作用 流程。此外,进一步阐明血管发育的生理调控机制,将 也确定未来可能的视网膜血管病变的治疗策略。
英文摘要
Project Summary Retinal blood vessel formation is a highly regulated process that requires multi-cellular crosstalk and interactions. Due to the complexity of retinal vascular development, there are several critical knowledge gaps that need to be addressed. For example, the key glial cell type that regulate retinal vascular development are astrocytes, which lay a template for blood vessel formation. Endothelial cells migrate over the spatially organized astrocytic template to form superficial blood vessels that give rise to three interconnected vascular layers in the mature retina. Disruption of the astrocytic template during development or loss of astrocyte association with blood vessels in adulthood can be detrimental to vascular growth, integrity, and function. The underlying cellular and molecular signaling mechanisms that regulate astrocyte spatial patterning and subsequent organized blood vessel formation during development remain incompletely understood. Elucidating the molecular mechanisms that govern blood vessel development and function is necessary to identify more targeted therapeutic strategies for blinding retinal vascular pathologies, and to identify which critical developmental processes should not be targeted in some contexts, for example retinopathy of prematurity. Our major goal is to delineate the signaling mechanisms that regulate astrocyte template spatial arrangement and vascular network formation. Our preliminary findings strongly support the rationale for the present study. Our RNA-seq data reveal that specific chemokine and complement gene expression levels are elevated during retinal vascular development. Intriguingly, deletion of one of the affected chemokine receptors disrupts astrocyte template formation and microglial recruitment and distribution. On the other hand, deletion of complement components results in an aberrantly dense astrocytic template and dysmorphic excessive tip cell formation. Based on these novel findings, we hypothesize that microglial chemokine signaling and complement activation are critical for normal retinal vascular development. We will refute or validate our hypothesis in the following two Specific Aims: Aim 1: To determine if chemokine signaling recruits microglia to modulate astrocyte template assembly. Aim 2: To define the role of complement receptors in astrocyte template and vascular network formation. We will utilize innovative multiplex RNA/protein based assays, novel ex vivo migration assays, unique reporter mice, and cre/lox animals for cell-specific deletion. We expect that successful completion of the proposed studies will identify novel roles for the innate immune system in regulating highly complex retinal vascular developmental processes. Moreover, further elucidating physiological regulatory mechanisms of vascular development, will also identify future putative therapeutic strategies for retinal vascular pathologies.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
Retinal Injury Activates Complement Expression in Müller Cells Leading to Neuroinflammation and Photoreceptor Cell Death.
视网膜损伤激活了导致神经炎症和感光细胞死亡的Müller细胞中的补体表达。
DOI: 10.3390/cells12131754
发表时间: 2023-06-30
期刊: CELLS
影响因子: 6
作者: [Tabor, Steven J. J., Yuda, Kentaro, Deck, Jonathan, Gnanaguru, Gopalan, Connor, Kip M. M.]
通讯作者: Connor, Kip M. M.
Innate Immunomodulation of Retinal Vascular Development
Innate Immunomodulation of Retinal Vascular Development
Sex dependent regulation of retinal degeneration
Sex dependent regulation of retinal degeneration
海外基金