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3-Dimensional Retinal Organoid Platform for the Study of Retinoblastoma

用于视网膜母细胞瘤研究的 3 维视网膜类器官平台

基本信息

批准号：
10263901
负责人：
JAMES WILLIAM HARBOUR
金额：
$ 49.28万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10263901
关键词：
3-Dimensional Address Affect Animal Model Animals Bar Codes Biocompatible Materials Biological Biological Models Biomimetics Bioreactors CRISPR/Cas technology Cells Child Clinical Management Clone Cells Culture Techniques Custom DNA sequencing Data Defect Dependence Developed Countries Developing Countries Development Disease Drug Targeting Embryo Engineering Environment Equilibrium Event Excision Eye Genes Genetic Genetic Transcription Genetically Engineered Mouse Health Human Hypoxia Invaded Knowledge Laboratories Lead Left Life Light Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Modeling Molecular Molecular Abnormality Mus Mutation Nature Neoplasm Metastasis Neural Retina Normal tissue morphology Nuclear Orphan Receptor Optic Nerve Organ Organoids Output Oxygen Parents Pathway interactions Patients Pattern Pharmacology Phase Phenotype Photoreceptors Physiological Procedures Proliferating RB1 gene Resolution Retina Retinal Cone Retinal Neoplasms Retinal Photoreceptors Retinoblastoma Rod Savings Seeds Stimulus Survival Rate System TP53 gene Technology Testing Therapeutic Time Tissue Engineering Tissues Tumor Suppressor Proteins Undifferentiated Vision Visual Visual impairment base bioinformatics pipeline cancer genomics cell type childhood cancer mortality clinical phenotype cost design differentiation protocol drug development druggable target estrogen-related receptor genetic analysis genetic corepressor genetic manipulation genomic aberrations human disease improved in silico in utero induced pluripotent stem cell malignant neoplasm of eye mouse model multidisciplinary mutant neoplastic cell new technology next generation p107 protein premalignant preservation psychologic retinal neuron retinal progenitor cell retinogenesis single-cell RNA sequencing social stigma stem cell biology targeted treatment therapeutic candidate tissue culture transcriptome sequencing tumor tumor progression

项目摘要

Project Summary/Abstract Retinoblastoma (Rb) is the most common eye cancer in children and a significant contributor to childhood cancer deaths worldwide. Rb tumors arise from biallelic loss of the RB1 gene during retinal development in-utero, and are uniformly lethal if left untreated. While clinical management of the tumor has advanced in recent decades, the non-specific and highly toxic nature of current therapies frequently result in life-long visual compromise and health complications. Similarly, the exorbitant cost and limited access to advanced procedures render the best treatment options inaccessible to most children worldwide, where eye removal remains the only life-saving option for patients. However, the social stigma and psychological effects of eye removal often lead parents to forego treatment, resulting in survival rates below 50% in many regions of the world. The most significant barrier to progress in developing targeted selective therapies for retinoblastoma is the gap in knowledge regarding the molecular drivers of retinoblastoma progression. Currently, no laboratory models exist, animal or otherwise, which faithfully recapitulate the human manifestation of this disease, and the limited amount of information available comes from tumors which necessitate removal, thus only providing a snapshot of the molecular mechanisms present in advanced cases. The ability to study these tumors in earlier stages, including their pre- malignant phase would shed light into the molecular drivers of Rb progression, lead to more targeted therapies which obviate the need for eye removal, ideally preserving vision but, more importantly, save lives. Recently, we have developed a human iPSC-based 3-Dimensional retinal organoid differentiation protocol and tissue culture bioreactor system in which we can control various environmental parameters critical for proper retinal development. Using this platform, we can use gene editing to introduce the most prevalent mutations found in Rb tumors and evaluate their effect on retinal development and tumor formation. We have shown how some of these mutations lead to amplification of a pre-malignant undifferentiated mutant cell clone, and disrupt terminal differentiation of other retinal cell types. We now propose to establish this platform as the first model system in which the various aspects of human Rb tumors can be elucidated, from their initiation through the drivers of malignant transformation. In order to achieve this, we aim to 1) Optimize, validate, and deploy our tissue bioreactor system to recapitulate the microenvironment of the developing retina, 2) use gene editing technology to establish the physiologic pattern of mutation acquisition during retinogenesis which leads to Rb tumor formation, and 3) use our 3D retinal organoid platform to screen pharmacological compounds that can address the molecular determinants of Rb tumor progression.

项目总结/文摘