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.

项目摘要 博士Olachi Mezu-Ndubuisi是一名眼科医生，曾接受验光师培训，现在是助理验光师。 儿科学教授，并在纽约大学眼科学系担任附属职务。 威斯康星州（UW）。她将这些经验结合在她的研究早产儿视网膜病变（ROP）。 ROP是早产儿视网膜血管异常的双相疾病，其特征在于： 血管内皮生长因子（VEGF）失调。ROP无法治愈，现有的治疗方法 不利的系统性影响和长期赤字。Mezu-Ndubuisi博士开发了一种非侵入性的方法， 使用荧光素在氧诱导的视网膜病变（OIR）的小鼠模型中可视化视网膜血管 动脉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）与视网膜血管病变之间的相关性进行了研究。 血管）的结构和功能，并进行了组织学研究，以显示独特的长期特征， OIR小鼠，如延长细胞凋亡，神经胶质激活，和异位形成的突触。具有 定义了体内和组织学OIR表型，她寻求使用分子技术来增强 了解ROP中VEGF的调节，以开发安全有效的治疗方法。在她的初步 研究中，在出生后第13天（P），即第2阶段早期，小鼠总Vegfa 164水平增加了6倍 与RA小鼠相比，OIR小鼠中的ROP，并且Vegfa 164 b在OIR中显示出比RA小鼠高1.3倍的趋势， P10（高氧期间视网膜血管闭塞的峰值）。这表明VEGF亚型的不平衡 发生在ROP中。然后，她持续给予VEGF-A165的促血管生成亚型VEGF-A165 a， 释放微粒，导致早期视网膜血管重建，改善动脉迂曲度和静脉 膨胀她接下来比较了局部骨化三醇（维生素D的活性形式）滴眼液和腹膜内（IP）骨化三醇 在II期ROP中，两种药物均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阶段早期使用玻璃体内VEGF-A165 a和局部使用VEGF-A165 a， 骨化三醇稍后在2期，将挽救异常的OIR在体内和组织学表型。在K 08中，博士。 Mezu-Ndubuisi将确定玻璃体内VEGF微粒或游离VEGF的最有效和最小毒性剂量。 玻璃体内注射VEGF蛋白和局部应用骨化三醇治疗2期ROP（Aim 1），探讨其分子机制 VEGF-A165 a和骨化三醇通过其调节ROP中的血管生成信号（Aim 2）。UW提供了一个很好的 学术环境，国家的最先进的设施，和学术资源致力于博士Mezu-Ndubuisi的 成功她有很强的校内和校外辅导，从完善的国家卫生研究院的研究人员， ROP、分子遗传学、血管生成和维生素D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，研究伦理和实验室技能。这将使她成功 过渡到研究独立和临床翻译她的研究。