Mechanisms of Retinal Vascular Permeability in Diabetes

糖尿病视网膜血管通透性的机制

基本信息

批准号：
8989102
负责人：
David Antonetti
金额：
$ 42.93万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8989102
关键词：
Animal Model Antibodies Blindness Blood Vessels Blood-Retinal Barrier Cell Culture Techniques Clinical Data Clinical Trials Complement Complex Cyclic AMP Cytoskeleton Data Development Diabetes Mellitus Diabetic Retinopathy Disease Endophthalmitis Endothelial Cells Fingers Funding Gene Targeting Goals Growth Guanine Nucleotide Exchange Factors Health Human Inflammatory Injection of therapeutic agent Interleukin-6 Laboratories Lead Ligands Link Mass Spectrum Analysis Medical Mitotic Modeling Molecular Monomeric GTP-Binding Proteins Nature Pathologic Neovascularization Pathology Pathway interactions Patients Permeability Phospho-Specific Antibodies Phosphorylation Phosphorylation Site Physiological Proliferating Property Protein Kinase C Proteins Publishing Regulation Research Retina Retinal Retinal Detachment Retinal Edemas Risk Role Sampling Signal Pathway Signal Transduction Site Small Interfering RNA TNF gene Testing Therapeutic Intervention Tight Junctions Transgenic Animals Transgenic Mice United States Vascular Diseases Vascular Endothelial Growth Factors Vascular Endothelium Vascular Permeabilities Viral Visual Acuity angiogenesis atypical protein kinase C base beta-Chemokines cytokine improved in vivo in vivo Model inducible gene expression innovation insight lymphotoxin beta macular edema mutant novel novel therapeutics nuclease occludin phosphoproteomics prevent response

项目摘要

DESCRIPTION (provided by applicant): Diabetic retinopathy remains a leading cause of blindness in the United States. Recent clinical trials have demonstrated that targeting vascular endothelial growth factor (VEGF) can effectively prevent progression of vision loss and for some patients restore visual acuity. These studies demonstrate that medical therapy for the retina can effectively treat diabetic retinopathy. However, not all patients respond to anti-VEGF therapies, which require repeat intra-ocular injections with the risk of endophthalmitis. In addition to VEGF, a number of inflammatory factors are elevated in patients with diabetic retinopathy that are believed to contribute to disease pathology including tumor necrosis factor, the chemokine (C-C motif) ligand 2 (CCL2), interleukin 6 and 8. Therefore, understanding the mechanisms by which growth factors and inflammatory cytokines alter the retinal vascular endothelium leading to vascular permeability and angiogenesis remains of high significance. Research from the previous funding period has identified two important signaling pathways that control permeability in response to VEGF. The first pathway involves conventional protein kinase C (PKC) activation and phosphorylation of the tight junction protein occludin and is required for VEGF induced vascular permeability. Published and preliminary data also reveal that occludin phosphorylation contributes to growth control and angiogenesis. Thus, occludin phosphorylation downstream of VEGF activation contributes to both vascular permeability and angiogenesis suggesting an important role in growth and blood-retinal barrier differentiation. Further, research over the previous funding period has identified a second signaling pathway involving atypical PKC activation as required for permeability response to both VEGF and inflammatory cytokines such as TNF and CCL2. Utilizing mass spectrometry phosphoproteomic analysis we have identified downstream targets linking this pathway to small G-protein regulation and control of permeability. Here we propose to define the role of occludin phosphorylation in permeability and angiogenesis in vivo while also elucidating the aPKC activation pathway to the control of vascular permeability. Collectively, these studies will provide novel insight into the mechanisms of VEGF induced permeability and angiogenesis specifically through the control of the tight junctions' complex and small G-protein regulation of the cytoskeleton. This research is expected to provide new insight into the nature of blood vessel growth and maturation and identify new targets for therapeutic intervention that are effective against both growth factors and inflammatory cytokines.

描述（由申请人提供）：糖尿病性视网膜病仍然是美国失明的主要原因。最近的临床试验表明，靶向血管内皮生长因子（VEGF）可以有效防止视力丧失进展，而对于某些患者，则可以恢复视力。这些研究表明，视网膜的药物治疗可以有效治疗糖尿病性视网膜病。但是，并非所有患者都对抗VEGF疗法做出反应，这些疗法需要重复的眼内注射，并具有内po的风险。除了VEGF，糖尿病性视网膜病患者的许多炎症因素被认为有助于疾病病理学，包括肿瘤坏死因子，趋化因子（C-C基序）配体2（CCL2），白介素6和8。意义。从上一个资金期开始的研究已经确定了两个重要的信号通路，以控制对VEGF的渗透率。第一个途径涉及传统的蛋白激酶C（PKC）激活和紧密连接蛋白闭塞的磷酸化，并且是VEGF诱导的血管通透性所必需的。已发表和初步数据还表明，闭塞磷酸化有助于生长控制和血管生成。因此，VEGF激活下游的闭合蛋白磷酸化有助于血管通透性和血管生成，这表明在生长和血液视网膜屏障分化中起重要作用。此外，在上一个资金期间的研究确定了第二种信号通路，涉及对VEGF和炎症细胞因子（例如TNF和CCL2）的渗透性反应所需的非典型PKC激活。利用质谱法磷酸蛋白质组学分析，我们已经确定了将该途径与小型G蛋白调节和渗透率控制相关的下游靶标。在这里，我们建议定义巴达丁磷酸化在体内渗透性和血管生成中的作用，同时还阐明了APKC激活途径以控制血管通透性。总的来说，这些研究将通过控制细胞骨架的紧密连接连接的复合复合物和小的G蛋白调节，以特别控制VEGF诱导的渗透性和血管生成的机理。预计这项研究将为血管生长和成熟的性质提供新的见解，并确定治疗干预措施的新靶标，这些靶标有效地抵抗生长因子和炎性细胞因子。