The role of plasmacytoid dendritic cells in ocular angiogenesis

浆细胞样树突状细胞在眼血管生成中的作用

基本信息

批准号：
9318784
负责人：
Pedram Hamrah
金额：
$ 43.75万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9318784
关键词：
Adoptive Cell Transfers Adoptive Transfer Affect Agonist Arteriosclerosis Blood Vessels Blood capillaries Bone Marrow Cell Proliferation Cell physiology Cells Choroidal Neovascularization Coculture Techniques Cornea Corneal Neovascularization Data Dendritic Cells Dichloromethylene Diphosphonate Disease Effectiveness Endostatins Endothelial Cells Enzyme-Linked Immunosorbent Assay Equilibrium Exhibits Extracellular Matrix Growth Factor Herpesvirus 1 Human Immune Immunofluorescence Immunologic In Vitro Inflammation Inflammatory Ischemia Keratitis Lasers Limb structure Link Lymphangiogenesis Maintenance Malignant Neoplasms Measures Mediating Messenger RNA Methods Microscopy Modeling Molecular Morphology Mus Myocardial Infarction Nerve Oxygen Participant Pathologic Pathologic Neovascularization Peptide Hydrolases Peptides Play Process Production Property Proteins Quantitative Reverse Transcriptase PCR Regulation Retina Retinal Retinal Diseases Retinal Neovascularization Role Simplexvirus Source Staining method Stains Stroke Structure of trigeminal ganglion TLR7 gene TLR9 gene Time Tissues Toll-like receptors Transplanted tissue Tube Vascular Endothelial Cell adaptive immune response angiogenesis attenuation capillary chemokine chronic wound clinically relevant density experimental study ganglion cell in vivo macrophage migration monocyte multi-photon neovascular neovascularization novel therapeutics ocular angiogenesis prevent small molecule transcriptome tumor

项目摘要

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.

项目概要血管生成受到生长因子、趋化因子、蛋白酶和炎症的平衡的精确调节细胞。巨噬细胞、单核细胞和传统树突状细胞 (cDC) 参与各个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形成。尽管这些细胞在血管生成中的功能已得到充分研究，但内源性细胞的作用和来源保留角膜血管生成特权或防止视网膜新生血管形成的抗血管生成分子是难以捉摸。此外，最近发现的浆细胞样树突状细胞（pDC）的影响，浆细胞样树突状细胞是存在于角膜和视网膜中的免疫细胞仍有待确定。这些细胞协调和联系先天性和适应性免疫反应，并参与诱导移植组织的耐受性或肿瘤。我们的初步实验表明，pDC 的耗竭伴随着突然和严重的角膜血管生成特权的破坏和角膜 pDCs 与内皮抑素（一种众所周知的抗-内皮抑素）共染色血管生成分子。我们假设 pDC 通过主动分泌抗血管生成药物来表现出抗血管生成功能。血管生成分子，对于保留角膜血管生成特权以及限制视网膜病理条件下的新生血管形成。我们的目标包括鉴定促血管生成和抗血管生成 pDC 表达的分子及其与角膜血管生成特权的功能相关性，表征 pDCs 对稳态和炎症期间角膜无血管状态的影响，描述参与 pDC 介导的角膜血管生成抑制的分子和细胞参与者新生血管形成，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单纯疱疹病毒（其天然激活剂）影响血管生成。此外，我们的目标是评估 pDC 在防止氧和激光诱导的损伤方面的影响。脉络膜新生血管并研究 pDC 过继转移治疗视网膜的有效性在这些情况下新生血管形成。该应用程序提出了我们理解的范式转变血管生成和角膜血管特权的调节。我们对 pDC 如何做出贡献的全新视角角膜的无血管状态和限制视网膜新血管形成的应用超出了眼组织。它可能会在各种病理条件下引入新的治疗途径，其中血管生成可能对癌症和炎症性疾病以及其他疾病有潜在益处诱导血管生成是有利的条件，特别是在缺血条件下。