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Role of retinoic acid signaling in fovea development

视黄酸信号在中央凹发育中的作用

基本信息

批准号：
10541865
负责人：
Susana Isabel M M A da Silva
金额：
$ 39.53万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10541865
关键词：
3-Dimensional Address Affect Age related macular degeneration Area Biological Models Birds Blindness Cell Therapy Cell Transplantation Chick Cone Data Development Disease Disease model Doxycycline Drug Screening Endowment Enzymes Experimental Models Face Gene Transfer Techniques Genetic Goals High Prevalence Human In Vitro Individual Macular degeneration Mammals Microscopy Molecular Organ Organoids Pathway interactions Pattern Primates Property Protocols documentation Reading Regulation Reporter Retina Retinal Diseases Rod Rodent Role Signal Transduction Source Speed Structure System Testing Transgenic Organisms Translating Tretinoin United States Vision Visual Acuity burden of illness clinically relevant density effective therapy fetal fovea centralis ganglion cell high resolution imaging high-throughput drug screening human stem cells in vitro Model in vivo induced pluripotent stem cell innovation insight macula model organism neural circuit novel pharmacologic programs retinogenesis societal costs spatiotemporal therapy development tool translational potential

项目摘要

PROJECT SUMMARY: The fovea is a highly specialized retinal structure located within the macula responsible for high- acuity vision, which in humans enables critical tasks such as reading and recognizing faces. Foveal diseases such as macular degeneration are highly debilitating and often lead to blindness. However, there are no current available treatments or therapies for fovea-specific disorders. A major reason underlying this limitation is the lack of suitable experimental systems for foveal studies, as only a small number of species have fovea-like high acuity areas (HAA). Indeed, among mammals, only a subset of primates has foveated retinas. However, avian species including the chick, possess fovea-like HAA and can be used as a powerful model system to study the molecular underpinnings of fovea formation in vivo. Human stem cell-derived retinal organoids (hRetOrg) have emerged as a promising in vitro system to study human retinal disorders but current protocols fail to generate foveae. We have recently found that retinoic acid (RA) signaling is highly patterned during foveogenesis in humans and is required for HAA formation in the chick. Our hypothesis is that recapitulation of endogenous patterns of RA signaling in hRetOrg is sufficient to induce fovea formation. To test this hypothesis, we will utilize the chick system to elucidate the spatiotemporal properties of RA-dependent fovea induction in vivo (Aim 1); longitudinally characterize the dynamics of RA signaling and expression profile of RA enzymes during retinogenesis period in hRetOrg (Aim 2); experimentally manipulate RA signaling to recapitulate the spatiotemporal patterns of RA found in vivo in the in vitro hRetOrg system (Aim 3). To achieve this we have developed an innovative molecular strategy based on transposon- and doxycycline-inducible systems for precise spatial and temporal regulation of transgenesis and optimized high-speed high-resolution imaging analysis of whole chick retinas and 3D hRetOrg. This effort will not only advance our current understanding of the mechanistic role of RA signaling as a fovea regulator but also generate an innovative and much needed foveated hRetOrg system with high translational potential for diseases affecting the fovea through disease modeling, high-throughput drug screening and as a source of clinically-relevant fovea-specific cells for transplantation.

项目总结: