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

基本信息

批准号：
10688094
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
项目类别：
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/10688094
关键词：
Ablation Adult Affect Age Air Angiogenesis Inhibitors Angiogenic Proteins Apoptosis Appointment Binding Biochemistry Biological Biometry Blindness Blood Vessels Blood capillaries Calcitriol Cataract Childhood Dedications 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 Ischemia Knowledge Laboratories 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 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 Visualization 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 particle postnatal preservation professor protein expression research study retina blood vessel structure retinal angiogenesis skills success synaptogenesis systemic toxicity therapeutically effective trend

项目摘要

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，其特征为血管内皮生长因子 (VEGF) 失调无法治愈，现有疗法已无法治愈。 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她将体内视网膜血管变化（动脉迂曲、静脉扩张和毛细血管）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。定义了体内和组织学 OIR 表型，她寻求利用分子技术来增强她初步了解了 ROP 中的 VEGF 调节，以便开发出安全有效的疗法。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。然后，她持续施用 VEGF-A165 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接下来，她将局部骨化三醇（维生素 D 的活性形式）滴眼剂与腹腔内 (IP) 骨化三醇进行了比较。两者均在第 2 期 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 Mezu-Ndubuisi 博士认为，在第 2 阶段早期和局部使用玻璃体内 VEGF-A165a。在第二阶段后期，骨化三醇将挽救体内和组织学表型的异常 OIR。 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（目标 2）。 Mezu-Ndubuisi 博士的学术环境、最先进的设施和学术资源她得到了美国国立卫生研究院 (NIH) 知名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将使她取得成功。过渡到研究独立性和研究的临床转化。