VEGF'S LONGITUDINAL EFFECT ON THE RETINA AND RETINAL VASCULATURE IN VIVO

VEGF 对体内视网膜和视网膜血管的纵向影响

• 批准号: 9022581
• 负责人: KENNETH PATRICK MITTON
• 金额: $ 44.85万
• 依托单位: OAKLAND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9022581
• 关键词: Address; Adverse effects; Affect; Age related macular degeneration; Anti-Inflammatory Agents; Anti-inflammatory; Automobile Driving; Binding; Biological Models; Blindness; Blood Circulation; Blood Vessels; Blood-Retinal Barrier; Cell Adhesion; Cell Communication; Cell Culture Techniques; Data; Diabetic Retinopathy; Disease; Drops; Dyes; Endothelial Cells; Evans blue stain; Event; Extracellular Matrix; Extravasation; Eye; Fluorescein Angiography; Future; Gene Expression; Gene Expression Profiling; Goals; Growth; Homeostasis; Human; Image; Immunoblotting; Inflammation; Inflammatory Response; Intravenous; Investigation; KDR gene; Knowledge; Label; Leukocytes; Life; MAP Kinase Gene; MAPK Signaling Pathway Pathway; Maintenance; Measures; Modeling; Molecular; Monitor; Neuropilin-1; North America; Optical Coherence Tomography; Pathway interactions; Perfusion; Pharmaceutical Preparations; Phospho-Specific Antibodies; Plasma; Process; Protein Isoforms; Rattus; Reporting; Research Proposals; Retina; Retinal; Retinal Diseases; Retinal Edemas; Retinal Neovascularization; Retinopathy of Prematurity; Safety; Serum; Signal Pathway; Signal Transduction; Stream; Suggestion; TNF gene; Testing; Therapeutic Uses; Tight Junctions; VEGF Trap; VEGFA gene; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular Permeabilities; angiogenesis; base; cell type; combat; in vivo; intercellular cell adhesion molecule; intravitreal injection; neovascular; neovascularization; novel therapeutics; physical model; public health relevance; receptor; undergraduate student

 DESCRIPTION (provided by applicant): VEGF-blocking therapy is used to treat neovascular proliferation and retinal edema in AMD and diabetic retinopathy. VEGF affects many processes, including: angiogenesis, vascular homeostasis, neovascularization, inflammatory response and disruption of the blood retinal barrier. Furthermore, several isoforms of VEGFA may drive either neovascularization or retinal edema (leaky blood vessels). VEGF-blocking drugs injected into the eye can enter the circulation and drop serum levels of VEGFA. Also, the safety of using VEGF-blockers for retinopathy of prematurity is unclear because treatment could block normal vessel growth. Thus, it is important to understand the mechanisms of VEGFA's action in the retina. Gaps remain in our knowledge because most investigations do not differentiate between the different isoforms of VEGFA. VEGFA-165 is an isoform that drives neovascular retinal disease. Recently, so-called "anti- angiogenic" b-isoforms of VEGFA were discovered including VEGFA-165b. There are suggestions that VEGFA-165b might be used therapeutically to counter retinal the neovascularization, but we don't know if VEGFA-165b causes vascular leakage like its regular isoform. We hypothesize that VEGFA-165b can still disrupt the blood retinal barrier and cause inflammation, regardless of its anti-angiogenic activity. In fact our preliminary data indicate this is so. To test this hypothesis, and with the involvement of numerous undergraduate students, we developed an intravitreal injection model (rat) to compare the effects of VEGFA-165 and -165b on the retinal vasculature. We will also use cultures of Human Retinal Endothelial Cells to compare the cell-signaling pathways activated by both isoforms in this cell-type. Results will increase our understanding of molecular events triggered by each VEGFA-165 isoform, and provide a model system with future application to study the efficacy and safely of new VEGF-modulating drugs.

 描述（通过应用提供）：使用VEGF阻滞疗法用于治疗AMD和糖尿病性视网膜病中的新血管增殖和视网膜水肿。 VEGF影响许多过程，包括：血管生成，血管稳态，新生血管形成，炎症反应和血液视网膜屏障的破坏。此外，VEGFA的几种同工型可能驱动新血管形成或视网膜水肿（漏水血管）。注入眼睛的VEGF阻断药物可以进入循环并降低血清VEGFA的水平。同样，使用VEGF阻滞剂进行早产性视网膜病变的安全性尚不清楚，因为治疗可能会阻止正常的血管生长。这是重要的是要了解Vegfa在视网膜中行动的机制。差距仍然存在于我们的知识中，因为大多数研究没有区分VEGFA的不同同工型。 VEGFA-165是一种驱动新血管视网膜疾病的同工型。最近，发现了包括VEGFA-165B在内的所谓的VEGFA的“抗血管生成” B-异型。有建议，VEGFA-165B可以在治疗上用于抵抗视网膜新血管形成，但我们不知道VEGFA-165B是否会像常规同工型一样引起血管泄漏。我们假设VEGFA-165B仍然可以破坏血液残留屏障并引起违反，而不论其抗血管生成活性如何。实际上，我们的初步数据表明是这样。为了检验这一假设，并在众多本科生的参与下，我们开发了玻璃体内注射模型（大鼠），以比较VEGFA -165和-165B对视网膜脉管系统的影响。我们还将使用人类视网膜内皮细胞的培养物比较该细胞类型中两种同工型激活的细胞信号途径。结果将增加我们对每种VEGFA-165同工型触发的分子事件的理解，并为未来的应用程序提供了一个模型系统，以研究新的VEGF调节药物的有效性和安全性。

项目成果

Differences in activation of intracellular signaling in primary human retinal endothelial cells between isoforms of VEGFA 165.

VEGFA 165 亚型之间原代人视网膜内皮细胞细胞内信号传导激活的差异。

• 发表时间: 2021
• 期刊: Molecular vision
• 影响因子: 2.2
• 作者: Dailey,Wendelin;Shunemann,Roberto;Yang,Fang;Moore,Megan;Knapp,Austen;Chen,Peter;Deshpande,Mrinalini;Metcalf,Brandon;Tompkins,Quentin;Guzman,AlvaroE;Felisky,Jennifer;Mitton,KennethP
• 通讯作者: Mitton,KennethP

Ocular coherence tomography image data of the retinal laminar structure in a mouse model of oxygen-induced retinopathy.

• DOI: 10.1016/j.dib.2017.09.075
• 发表时间: 2017-12
• 期刊: Data in brief
• 影响因子: 1.2
• 作者: Dailey WA;Drenser KA;Wong SC;Cheng M;Vercellone J;Roumayah KK;Feeney EV;Deshpande M;Guzman AE;Trese M;Mitton KP
• 通讯作者: Mitton KP