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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：
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
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/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

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.

项目总结