Mechanism of intravitreal VEGF-A165a and topical calcitriol for the treatment of retinopathy of prematurity

玻璃体内注射VEGF-A165a联合局部骨化三醇治疗早产儿视网膜病变的机制

• 批准号: 10645643
• 负责人: Olachi Joy Mezu-Ndubuisi
• 金额: $ 23.61万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645643
• 关键词: Adult; Affect; Age; Air; Angiogenic Proteins; Apoptosis; Appointment; Binding; Biochemistry; Biological; Biometry; Blindness; Blood Vessels; Blood capillaries; Calcitriol; Cataract; Childhood; Diabetes Mellitus; Disease; Dose; Electroretinography; Endothelial Growth Factors Receptor; Environment; Equilibrium; Extramural Activities; Eye diseases; Eyedrops; Fluorescein Angiography; Genes; Goals; Growth; Growth Factor; Half-Life; Histologic; Histopathology; Human; Hyperoxia; Knowledge; Laboratories; Lead; Longitudinal Studies; Low-Level Laser Therapy; Malignant Neoplasms; Measures; Mediating; Mentors; Methods; Molecular; Molecular Genetics; Monoclonal Antibodies; Mus; Ophthalmology; Optical Coherence Tomography; Optometrist; Oxygen; Pathogenesis; Pathway interactions; Patients; Pediatrics; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase Transition; Phenotype; Premature Infant; Protein Isoforms; Protein Kinase; Proteins; RNA Splicing; Refractive Errors; Regulation; Research; Research Ethics; Research Personnel; Resources; Retina; Retinal Detachment; Retinal Diseases; Retinopathy of Prematurity; Role; Signal Transduction; Signaling Protein; Structure; Synapses; Techniques; Testing; Therapeutic; Thick; Toxic effect; Training; Translational Research; United States; United States National Institutes of Health; Universities; VEGFA gene; Variant; Vascular Endothelial Growth Factors; Vascularization; Veins; Venous; Vision; Visual; Visual Fields; Vitamin D; Vulnerable Populations; Wisconsin; angiogenesis; arterial tortuosity; bevacizumab; career; central retinal artery; clinical translation; effective therapy; experience; glial activation; histological studies; improved; in vivo; innovation; intraperitoneal; intravitreal injection; mouse model; neovascularization; novel; novel therapeutics; overexpression; postnatal; preservation; professor; protein expression; research study; retina blood vessel structure; retinal angiogenesis; skills; success; synaptogenesis; systemic toxicity; therapeutically effective; trend

PROJECT SUMMARY Dr. Olachi Mezu-Ndubuisi is a neonatologist with a background training as an optometrist, now an Assistant Professor of Pediatrics with an affiliate appointment in the Department of Ophthalmology at University of Wisconsin (UW). She combines these experiences in her research studying Retinopathy of Prematurity (ROP). ROP is a bi-phasic disease of abnormal retinal vascularization in premature infants, characterized by dysregulation of vascular endothelial growth factor (VEGF). ROP has no cure, and existing therapies have adverse systemic effects and long-term deficits. Dr. Mezu-Ndubuisi developed a non-invasive method of visualizing retinal blood vessels in a mouse model of oxygen-induced retinopathy (OIR) using fluorescein angiography. She correlated in vivo retinal vascular changes (arterial tortuosity, venous dilation, and capillary vascularity) to structure and function, and performed histological studies to show unique long-term features of OIR mice, such as prolonged cellular apoptosis, glial activation, and ectopic formation of synapses. Having defined the in vivo and histologic OIR phenotypes, she seeks to use molecular techniques to enhance understanding of VEGF regulation in ROP in order to develop safe and effective therapies. In her preliminary studies, there was a 6-fold increase in total mouse Vegfa164 levels at post-natal day (P) 13, early in Phase 2 ROP, in OIR mice compared to RA mice, and Vegfa164b showed a 1.3-fold higher trend in OIR than RA mice at P10 (peak of retinal vaso-obliteration during hyperoxia). This suggests that an imbalance of VEGF isoforms occurs in ROP. She then administered the pro-angiogenic isoform of VEGF-A165, VEGF-A165a, in sustained release microparticles which resulted in earlier retinal revascularization with improved arterial tortuosity and vein dilation. She next compared topical calcitriol (active form of vitamin D) eyedrop to intraperitoneal (IP) calcitriol and both inhibited retinal angiogenesis later in Phase 2 ROP, but topical calcitriol did not cause growth restriction like IP calcitriol. Dr. Mezu-Ndubuisi hypothesizes that using intravitreal VEGF-A165a early in Phase 2 and topical calcitriol later in Phase 2, would rescue the abnormal OIR in vivo and histologic phenotypes. In this K08, Dr. Mezu-Ndubuisi will determine the most effective and least toxic dose of intravitreal VEGF microparticles or free intravitreal VEGF protein and topical calcitriol in Phase 2 ROP (Aim 1), and then study the molecular mechanisms by which VEGF-A165a and calcitriol regulate angiogenic signaling in ROP (Aim 2). UW provides an excellent academic environment, state-of-the-art facilities, and academic resources dedicated to Dr. Mezu-Ndubuisi’s success. She has strong intra-mural and extra-mural mentoring from well-established NIH investigators and experts in ROP, molecular genetics, angiogenesis, and Vitamin D. Dr. Mezu-Ndubuisi’s career goals and objectives include a detailed training plan to increase her knowledge in biostatistics, biochemistry, histopathology, molecular signaling, and research ethics and laboratory skills. This will enable her successful transition to research independence and clinical translation of her research.

项目概要 Olachi Mezu-Ndubuisi 博士是一名新生儿科医生，接受过验光师背景培训，现为助理 英国大学眼科系儿科教授 威斯康星州（UW）。她将这些经验结合到了早产儿视网膜病变 (ROP) 的研究中。 ROP是早产儿视网膜血管化异常的双相性疾病，其特征是 血管内皮生长因子（VEGF）失调。 ROP 无法治愈，现有疗法已无法治愈 不良的系统性影响和长期赤字。 Mezu-Ndubuisi 博士开发了一种非侵入性方法 使用荧光素观察氧诱导视网膜病变 (OIR) 小鼠模型中的视网膜血管 血管造影。她将体内视网膜血管变化（动脉迂曲、静脉扩张和毛细血管扩张）关联起来。 血管分布）到结构和功能，并进行组织学研究以显示独特的长期特征 OIR 小鼠，例如细胞凋亡延长、神经胶质激活和突触异位形成。拥有 定义了体内和组织学 OIR 表型，她寻求利用分子技术来增强 了解 ROP 中 VEGF 的调节，以便开发安全有效的治疗方法。在她的初步 研究显示，在第 2 阶段早期，出生后第 13 天 (P) 时，小鼠 Vegfa164 总水平增加了 6 倍 OIR 小鼠中的 ROP 与 RA 小鼠相比，Vegfa164b 在 OIR 中的趋势比 RA 小鼠高 1.3 倍 P10（高氧期间视网膜血管闭塞的峰值）。这表明 VEGF 亚型不平衡 发生在 ROP 中。然后，她持续施用 VEGF-A165 的促血管生成异构体 VEGF-A165a。 释放微粒，导致早期视网膜血运重建，改善动脉和静脉曲折 扩张。接下来，她将外用骨化三醇（维生素 D 的活性形式）滴眼剂与腹膜内 (IP) 骨化三醇进行了比较 两者均在第 2 阶段 ROP 后期抑制视网膜血管生成，但局部骨化三醇不会导致生长受限 如IP骨化三醇。 Mezu-Ndubuisi 博士假设，在第 2 期早期和局部使用玻璃体内 VEGF-A165a 第二阶段后期的骨化三醇将挽救体内异常的 OIR 和组织学表型。在这个 K08 中，博士。 Mezu-Ndubuisi 将确定玻璃体内 VEGF 微粒或游离的最有效且毒性最小的剂量 玻璃体内 VEGF 蛋白和局部骨化三醇在第 2 期 ROP（目标 1）中，然后研究分子机制 VEGF-A165a 和骨化三醇通过其调节 ROP 中的血管生成信号传导（目标 2）。 UW 提供了极好的 Mezu-Ndubuisi 博士的学术环境、最先进的设施和学术资源 成功。她得到了来自知名 NIH 研究人员的强有力的校内和校外指导， ROP、分子遗传学、血管生成和维生素 D 方面的专家。Mezu-Ndubuisi 博士的职业目标和 目标包括详细的培训计划，以增加她在生物统计学、生物化学、 组织病理学、分子信号传导、研究伦理和实验室技能。这将使她成功 过渡到研究独立性和研究的临床转化。