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

• 批准号: 9893891
• 负责人: Pedram Hamrah
• 金额: $ 49.56万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893891
• 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; Keratitis; Lasers; 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 Diseases; Retinal Neovascularization; Role; Simplexvirus; Source; Stains; Stroke; Structure of trigeminal ganglion; TLR7 gene; TLR9 gene; Time; Tissue Transplantation; Tissues; Toll-like receptors; Tube; Vascular Endothelial Cell; adaptive immune response; angiogenesis; attenuation; chemokine; chronic wound; clinically relevant; density; experimental study; ganglion cell; in vivo; limb ischemia; macrophage; migration; monocyte; multi-photon; neovascular; neovascularization; novel therapeutics; ocular angiogenesis; preservation; prevent; small molecule; transcriptome; tumor

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.

项目摘要 血管生成受到生长因子、趋化因子、蛋白水解酶和炎症的精确调节。 细胞。巨噬细胞、单核细胞和常规树突状细胞(CDCs)参与了所有阶段的 从局部细胞外基质降解到内皮细胞和毛细血管增殖的血管生成 队形。尽管这些细胞在血管生成中的功能已经研究得很好，但内源性的作用和来源 维持角膜血管生成特权或防止视网膜新生血管的抗血管生成分子 难以捉摸。此外，最近发现的浆细胞样树突状细胞(PDCs)的影响，一个重要的亚群 驻留在角膜和视网膜中的免疫细胞仍有待确定。这些细胞协调和连接 先天和获得性免疫反应与诱导移植组织耐受有关 或者肿瘤。我们的初步实验表明，pDC的枯竭伴随着突然和严重的 内皮抑素对角膜和角膜PDCs血管生成特权的破坏作用 血管生成分子。我们推测PDCs通过主动分泌抗血管生成因子发挥抗血管生成功能。 血管生成分子，是保持角膜血管生成特权和限制视网膜所必需的 病理条件下的新生血管。我们的目标包括鉴定促血管生成和抗血管生成 PDCs表达的分子及其在角膜血管生成特权中的功能相关性 描述了PDCs在稳态和炎症期间对角膜无血管状态的影响 PDC抑制角膜新生血管形成的分子和细胞机制 新生血管形成，并评估pDC如何通过激活Toll样受体(TLR)-7和 TLR-9通过它们的合成激动剂以及它们的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PDCs在防止氧气和激光诱导方面的影响。 脉络膜新生血管及PDCs过继移植治疗视网膜的疗效研究 在这些条件下的新生血管。这个应用程序提出了我们对 血管生成的调节和角膜血管特权。我们对pdc如何做出贡献的新视角 角膜的无血管状态和限制视网膜新生血管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，在这些条件下， 血管生成可能是有益的，例如癌症和炎症性疾病，以及 诱导血管生成是有利的条件，特别是在缺血条件下。