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Cyr61/CCN1-Induced Angiogenesis and Vasculogenesis in the Retina

Cyr61/CCN1 诱导的视网膜血管生成

基本信息

批准号：
7911702
负责人：
BRAHIM CHAQOUR
金额：
$ 22.19万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7911702
关键词：
Ablation Acute Address Adhesions Adhesives Age related macular degeneration Anoikis Apoptosis Binding Proteins Biological Biological Process Blood Vessels Blood capillaries Bone Marrow C-terminal CD34 gene Cell Culture Techniques Cell Proliferation Cells Cessation of life Characteristics Complex Cultured Cells Cystine Cystine Knot Motifs Defect Development Diabetic Retinopathy Disease Embryo Endothelial Cells Ensure Environment Event Extracellular Matrix Extracellular Matrix Proteins Eye diseases Family Gene Expression Gene Family Genes Growth Hemorrhage Heparin In Vitro Individual Inflammation Injection of therapeutic agent Injury Insulin-Like Growth-Factor-Binding Proteins Integrin Binding Integrins Laboratories Lentivirus Vector Link Mediating Modeling Molecular Mononuclear Mus N-terminal Neonatal Oxygen Pathogenesis Pathologic Neovascularization Pericytes Pharmacotherapy Phenotype Population Process Property Protein Binding Recovery Retina Retinal Retinal Diseases Retinopathy of Prematurity Role SCID Mice Signal Transduction Site Source Stem cells Structure-Activity Relationship Tertiary Protein Structure Thrombospondin 1 Undifferentiated Vascular Diseases Vascularization Venous Work alternative treatment angiogenesis base capillary capillary bed cell growth cell type central retinal vein occlusion cyr61 protein design expectation extracellular improved in vivo member migration mouse model neonate neovascular neovascularization novel polypeptide postnatal precursor cell progenitor proliferative diabetic retinopathy public health relevance receptor repaired response retina blood vessel structure retinal apoptosis retinal progenitor cell therapeutic angiogenesis vasculogenesis von Willebrand Factor

项目摘要

DESCRIPTION (provided by applicant): Development and remodeling of retinal blood vessels occurs through the complex and still poorly understood processes of vasculogenesis and angiogenesis. These processes are recapitulated, though imperfectly, in the context of ischemic injury associated with numerous ocular diseases, (e.g., retinopathy of prematurity, age-related macular degeneration, diabetic retinopathy, etc). The pathogenesis of these retinal neovascular disorders is driven by a pathological angiogenesis leading to the formation of abnormal vessels, which break into the vitreous, and an insufficient/limited vasculogenesis in which the cellular components of the new vessel complex originate in part, from bone-marrow (BM) derived circulating vascular progenitor cells. Components of the vascular extracellular matrix (ECM) coordinate the execution of multiple angiogenic and vasculogenic activities. Recent work in the PI's laboratory have revealed that the cysteine-rich protein 61 (Cyr61), a novel ECM-associated, heparin- and integrin-binding protein, stimulates the angiogenic phenotype of the BM-derived hematopoeitic progenitors, CD34+ cells. However, when exposed to cultured retinal pericytes, which sheath and regulate the growth of retinal capillaries, Cyr61 induces their death by anoikis suggesting a role of Cyr61 in pathological angiogenesis. The current proposal consists of a strategy to tease out these disparate activities of the Cyr61 protein both in vitro and in vivo. We will aim to determine that the multiple activities of Cyr61 are linked to its multi-modular organization consisting of 4 distinct domains: an insulin-like growth factor binding protein (IGFBPs) domain, the von Willebrand factor type C (vWFC) repeat, the thrombospondin type I (TSP1) repeat and a C-terminal (CT) cystine-knot motif. We predict that the N-terminal region containing IGFBP and/or vWFC domains with integrin-binding capabilities retains the angiogenic potential of Cyr61 vis-`-vis the CD34+ cells and promote their adhesion, migration, differentiation, and angiogenic activity. Conversely, the C-terminal region containing the TSP1 and/or CT domains induces apoptosis of retinal pericytes by virtue of its anti-adhesive properties. We will reveal these activities, in Specific Aim 1 using undifferentiated hematopoeitic CD34+ cells and cultured retinal pericytes exposed to recombinantly produced domains of Cyr61 or lentiviral vectors expressing the N-terminal or C- terminal regions. In Specific Aim 2, we will utilize the neonate mouse model of oxygen-induced retinopathy characterized by vaso-obliteration of the central retinal capillary bed to determine whether administration of either Cyr61 or Cyr61 modules promotes vascular repair by enhancing recruitment of EPCs to retinal sites of ischemic injury. Similarly, we will establish whether, BM-derived CD34+ cells, when primed with the N- terminal domains of Cyr61, integrate into damaged retinal vessels and improve vascular recovery. Our studies will help establish treatment alternatives for the diminished/limited vasculogenic capability in ischemic retinopathy and the specific contribution of truncated ECM proteins to EPC mobilization and recruitment. PUBLIC HEALTH RELEVANCE: Neovascularization of the retina is a highly prevalent and potentially blinding disorder characteristic of a variety of ocular diseases including diabetic retinopathy, age-related macular degeneration, central retinal vein occlusion, and retinopathy of permaturity. Our studies address the role of a specific component of the extracellular environment in retinal vessels and its ability to either facilitate or antagonize retinal vascular repair/rescue. Results of our studies will determine how specific portions of such extracellular compound can be used/modified to allow the formation of normally functioning retinal blood vessels and improve the pharmacotherapy of several retinal diseases.

描述（由申请人提供）：视网膜血管的发育和重塑是通过复杂的血管发生和血管生成过程发生的，但目前仍知之甚少。这些过程在与许多眼部疾病相关的缺血性损伤的背景下被概括，尽管不完全，（例如，早产儿视网膜病、年龄相关性黄斑变性、糖尿病视网膜病等）。这些视网膜新生血管性病症的发病机理是由病理性血管生成和不充分/有限的血管发生驱动的，病理性血管生成导致异常血管的形成，所述异常血管破裂到玻璃体中，在所述血管发生中，新血管复合体的细胞组分部分源自骨髓（BM）来源的循环血管祖细胞。血管细胞外基质（ECM）的成分协调多种血管生成和血管生成活动的执行。PI实验室的最新工作表明，富含半胱氨酸的蛋白61（Cyr 61），一种新的ECM相关的肝素和整合素结合蛋白，刺激BM衍生的造血祖细胞，CD 34+细胞的血管生成表型。然而，当暴露于培养的视网膜周细胞，鞘和调节视网膜毛细血管的生长，Cyr 61诱导其死亡的失巢凋亡表明Cyr 61在病理性血管生成的作用。目前的建议包括一个战略，梳理出这些不同的活动Cyr 61蛋白在体外和体内。我们的目标是确定Cyr 61的多种活动与其由4个不同结构域组成的多模块组织有关：胰岛素样生长因子结合蛋白（IGFBPs）结构域，血管性血友病因子C型（vWFC）重复序列，血小板反应蛋白I型（TSP 1）重复序列和C末端（CT）胱氨酸结基序。我们预测，含有IGFBP和/或vWFC结构域的N-末端区域具有整合素结合能力，保留了Cyr 61维斯维斯CD 34+细胞的血管生成潜力，并促进其粘附、迁移、分化和血管生成活性。相反，含有TSP 1和/或CT结构域的C-末端区域凭借其抗粘附特性诱导视网膜周细胞的凋亡。我们将在特异性目标1中使用未分化的造血CD 34+细胞和培养的视网膜周细胞暴露于重组产生的Cyr 61结构域或表达N-末端或C-末端区域的慢病毒载体来揭示这些活性。在具体目标2中，我们将利用以中央视网膜毛细血管床的血管闭塞为特征的氧诱导的视网膜病变的新生小鼠模型来确定Cyr 61或Cyr 61模块的施用是否通过增强EPC向缺血性损伤的视网膜部位的募集来促进血管修复。类似地，我们将确定当用Cyr 61的N末端结构域引发时，BM衍生的CD 34+细胞是否整合到受损的视网膜血管中并改善血管恢复。我们的研究将有助于建立缺血性视网膜病变血管生成能力减弱/受限的治疗方案，以及截短的ECM蛋白对EPC动员和招募的具体贡献。公共卫生相关性：视网膜的新生血管形成是多种眼部疾病的特征性的高度流行和潜在致盲的病症，所述眼部疾病包括糖尿病性视网膜病、年龄相关性黄斑变性、视网膜中央静脉阻塞和过成熟性视网膜病。我们的研究解决了视网膜血管中细胞外环境的特定组分的作用及其促进或拮抗视网膜血管修复/拯救的能力。我们的研究结果将确定如何使用/修饰这种细胞外化合物的特定部分，以形成功能正常的视网膜血管，并改善几种视网膜疾病的药物治疗。