A Next Generation Outer Retinal Microphysiological System

下一代外视网膜微生理系统

基本信息

批准号：
10444742
负责人：
Robert Foster Mullins
金额：
$ 38.63万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444742
关键词：
3-Dimensional 3D Print Age related macular degeneration Architecture Autologous Biological Models Biomimetics Blindness Cell Communication Cell Culture Techniques Cells Cessation of life Complex Custom Degenerative Disorder Deposition Development Disease Dropout Drusen Endothelial Cells Engineering Functional disorder Future Genes Hereditary Disease Human Individual Inherited Microfluidics Modeling Mutation Nervous system structure Neural Retina Nuclear Organoids Patients Perfusion Photoreceptors Polymers Retina Retinal Degeneration Scientist System Testing Tissue Differentiation Tissue Donors Tissues Validation cell type differentiation protocol disease mechanisms study drug development drug testing human model in vitro Model induced pluripotent stem cell induced pluripotent stem cell technology lithography microphysiology system monolayer next generation novel therapeutics programs scaffold single-cell RNA sequencing therapeutic gene two-photon ultra high resolution

项目摘要

ABSTRACT The discovery of induced pluripotent stem cells (iPSCs) provided scientists with the opportunity to develop differentiated tissues from patients with inherited disease, and to use these in vitro models to study disease mechanisms and to test drug and gene-based therapeutics. However, current differentiation protocols often fail to accurately recapitulate the cellular organization present in the native tissue. For example, even state-of-the- art retinal differentiation protocols, which give rise to three dimensional retinal organoids, do not accurately recapitulate the cell-cell interactions that are present in the outer retina. Specifically, choroidal endothelial cells are rarely present and never form an organized layer beneath the RPE. Similarly, rather than forming a monolayer juxtaposed to newly developed photoreceptors, RPE cells are often found in clusters located at the edges of the neural retina. In this application we describe a program focused on the development and validation of a microphysiological system engineered to accurately recreate the complex architecture of the perfused outer retina. Specifically, we propose to combine ultra-high resolution, state-of-the-art 3D printing of retinal scaffolds, iPSC technology, and microfluidics to develop a next generation microphysiological system that recapitulates the outer retina unit. Completion of the aims outlined in this proposal will help pave the way for future studies focused on evaluating the pathophysiology of complex retinal degenerative disorders such as age-related macular degeneration and development of novel drug and gene-based therapeutics.

抽象的诱导多能干细胞（iPSC）的发现为科学家提供了开发从患有遗传性疾病的患者中分化出组织，并使用这些体外模型来研究疾病机制并测试基于药物和基因的疗法。然而，当前的分化方案经常失败准确地再现天然组织中存在的细胞组织。例如，即使是最先进的产生三维视网膜类器官的艺术视网膜分化方案不能准确地概括了外视网膜中存在的细胞与细胞的相互作用。具体而言，脉络膜内皮细胞细胞很少存在，也不会在 RPE 下方形成有组织的层。同样，与其形成一个单层 RPE 细胞与新发育的光感受器并列，通常以簇状形式存在于神经视网膜的边缘。在此应用程序中，我们描述了一个专注于开发和验证微生理系统，旨在准确地重建复杂的结构外视网膜灌注。具体来说，我们建议将超高分辨率、最先进的 3D 打印技术与视网膜支架、iPSC 技术和微流体技术开发下一代微生理系统概括了外视网膜单位。完成本提案中概述的目标将有助于铺平道路未来的研究重点是评估复杂的视网膜退行性疾病的病理生理学，例如年龄相关性黄斑变性以及新药和基因疗法的开发。