The role of plasmacytoid dendritic cells in ocular angiogenesis

项目摘要 血管生成受到生长因子、趋化因子、蛋白酶和炎性因子的平衡的精确调节。 细胞巨噬细胞、单核细胞和常规树突状细胞（cDC）参与免疫反应的所有阶段。 血管生成从局部细胞外基质的降解到内皮细胞和毛细血管的增殖 阵尽管对这些细胞在血管生成中的功能进行了充分的研究，但内源性血管生成的作用和来源仍然是未知的。 保护角膜血管生成豁免或防止视网膜新生血管形成的抗血管生成分子， 难以捉摸。此外，最近发现的浆细胞样树突状细胞（pDC）的影响， 角膜和视网膜中的免疫细胞，仍有待确定。这些细胞协调并连接 先天性和适应性免疫应答，并与对移植组织的耐受性的诱导有关 或肿瘤。我们的初步实验表明，pDC的耗尽伴随着突然和严重的细胞凋亡。 角膜和角膜pDC血管生成豁免的破坏与内皮抑素共染色，内皮抑素是一种众所周知的抗 血管生成分子我们假设pDC通过主动分泌抗血管生成抗体来显示抗血管生成功能。 血管生成分子，并且对于保持角膜血管生成豁免以及限制视网膜血管生成是必需的。 病理条件下的新血管形成。我们的目标包括鉴定促血管生成和抗血管生成的 pDC表达的分子及其与角膜血管生成豁免的功能相关性，表征 pDC在稳态和炎症期间对角膜无血管状态的影响，描述了 参与pDC介导的角膜血管生成抑制的分子和细胞参与者 新血管形成，并评估如何通过激活Toll样受体（TLR）-7和 TLR-9通过其合成激动剂以及其天然激活剂单纯疱疹病毒影响 血管生成此外，我们的目标是评估pDC在防止氧诱导以及激光诱导的肿瘤细胞凋亡中的作用。 脉络膜新生血管形成和研究过继转移pDC用于治疗视网膜新生血管的有效性。 新血管形成。该申请提出了一个范式转变，我们的理解， 调节血管生成和角膜血管特权。我们对pDC如何有助于 角膜无血管状态和限制视网膜新血管形成具有超出眼组织的应用。它 将潜在地在各种病理状况中引入新的治疗途径， 血管生成对于诸如癌症和炎性疾病的治疗是潜在有益的， 诱导血管生成是有利的条件，特别是在缺血条件下。

Project Summary Angiogenesis is precisely regulated by a balance of growth factors, chemokines, proteases, and inflammatory cells. Macrophages, monocytes, and conventional dendritic cells (cDCs) are involved in all stages of angiogenesis from degradation of local extracellular matrix to proliferation of endothelial cells and capillary formation. Despite the well-studied functions of these cells in angiogenesis, the role and source of endogenous anti-angiogenic molecules which preserve corneal angiogenic privilege or prevent retinal neovascularization is elusive. Moreover, the impact of recently identified plasmacytoid dendritic cells (pDCs), a vital subset of immune cells that reside in the cornea and retina, remains to be determined. These cells orchestrate and link innate and adaptive immune responses and are implicated in the induction of tolerance to transplanted tissues or tumors. Our preliminary experiments showed that depletion of pDCs is accompanied by abrupt and severe breakdown of angiogenic privilege of cornea and corneal pDCs co-stain with Endostatin, a well-known anti- angiogenic molecule. We hypothesize that pDCs exhibit anti-angiogenic functions by actively secreting anti- angiogenic molecules and are necessary for preserving corneal angiogenic privilege as well as limiting retinal neovascularization in pathologic conditions. Our aims include identification of pro- and anti-angiogenic molecules expressed by pDCs and their functional relevance on corneal angiogenic privilege, characterizing the impact of pDCs on the avascular state of the cornea in steady-state and during inflammation, describing the molecular and cellular participants involved in pDC-mediated inhibition of corneal angiogenesis during neovascularization, and assessing how activation of pDCs through activation of toll like receptors (TLR)-7 and TLR-9 via their synthetic agonists as well as Herpes Simplex Virus, their natural activator, affects angiogenesis. Further, we aim to assess the impact of pDCs in preventing oxygen- as well as laser-induced choroidal neovascularization and study the effectiveness of adoptive transfer of pDCs for treatment of retinal neovascularization in these conditions. The application proposes a paradigm shift in our understanding of the regulation of angiogenesis and corneal vascular privilege. Our fresh perspective on how pDCs contribute to avascular state of cornea and restrict retinal neovascularization has applications beyond ocular tissues. It would potentially introduce new therapeutic avenues in various pathologic conditions in which attenuation of angiogenesis would be potentially beneficial such as cancers and inflammatory diseases, as well as in conditions which induction of angiogenesis is advantageous, particularly in ischemic conditions.