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Molecular mechanisms of retinogeniculate circuit formation

视网膜原路形成的分子机制

基本信息

批准号：
10192727
负责人：
MICHAEL A FOX
金额：
$ 36.84万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10192727
关键词：
Affect American Anatomy Axon Blindness Brain Brain region Candidate Disease Gene Cell Nucleus Cells Coculture Techniques Complex Cues Data Dendrites Dependovirus Development Disease Dorsal Economic Burden Electrophysiology (science)Eye diseases Fostering Funding Genes Glaucoma Goals Growth Histologic IGF1R gene Immunohistochemistry In Vitro Individual Injections Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Interneurons Knowledge Label Lateral Geniculate Body Leucine-Rich Repeat Mind Molecular Molecular Genetics Mus National Eye Institute Natural regeneration Nerve Nerve Degeneration Neuroglia Neurons Patients Persons Phenotype Physiological Population Proteins Recombinant IGF-I Recombinants Reporter Research Retina Retinal Ganglion Cells Role Signal Transduction Somatomedins Swimming Synapses Techniques Testing Thalamic structure Transgenic Organisms Validation Viral Vision Visual Visual impairment Work age related base cost design effective therapy experimental study mutant novel regenerative therapy relating to nervous system response retinal axon retinogeniculate sight restoration social superior colliculus Corpora quadrigemina synaptogenesis transcriptome sequencing viral rescue visual information

项目摘要

Developmental and age-related disorders that affect vision impart a major social and economic burden on the US economy. Many of these disorders specifically affect neurons that connect the retina (i.e., retinal ganglion cells [RGCs]) information to the brain. The most common of these disorders is glaucoma, a progressive neurodegenerative eye disorder that is the leading cause of irreversible blindness in the US. Currently, 3 million Americans are living with glaucoma, costing the US economy nearly 3 billion dollars each year. Glaucoma is not the only disorder that impacts RGCs. Currently there are no effective treatments for patients with glaucoma. In response to this unmet need, NEI has issued a goal of gaining new knowledge that will contribute to the development of regenerative therapies aimed at restoring connections between the retina and brain. To accomplish this goal, we need a better understanding of the mechanisms that drive the formation of these connections during normal development. Over the past 5 years, we investigated the mechanisms that drive the growth of retinal axons into appropriate target regions of brain. During this work, we discovered that retinal synapses in the dorsal lateral geniculate nucleus (dLGN) are anatomically and functionally distinct from retinal synapses in all other retino-recipient regions. Because these synapses are crucial for transmitting visual information to cortex, understanding mechanisms of their formation is essential for restoring subcortical visual circuit function. With this in mind, the objective of this application aims to identify target-derived cues responsible for the unique development of retinogeniculate synapses in dLGN. Preliminary experiments identified Insulin-like Growth Factor 1 (IGF1) and Leucine-Rich Repeat Transmembrane Neuronal Protein 1 (LRRTM1) as two synaptogenic cues expressed in dLGN. Here will will use molecular, genetic, anatomical and physiological approaches to assess roles of these molecules in retinogeniculate circuit formation.

影响视力的发育和年龄相关疾病给老年人带来了重大的社会和经济负担美国经济。其中许多疾病特别影响连接视网膜的神经元(即视网膜神经节细胞[RGCs])信息传给大脑。这些疾病中最常见的是青光眼，一种进行性青光眼神经退行性眼病是美国不可逆转失明的主要原因。目前，有3个数百万美国人患有青光眼，每年给美国经济造成近30亿美元的损失。青光眼并不是唯一影响视网膜节细胞的疾病。目前还没有对患者有效的治疗方法患有青光眼。为了回应这一未得到满足的需求，NEI发布了一个目标，即获得新的知识，将帮助开发旨在恢复视网膜和视网膜之间连接的再生疗法大脑。为了实现这一目标，我们需要更好地了解推动形成在正常发育过程中的这些连接。在过去的5年里，我们研究了推动视网膜轴突生长到大脑中适当的靶区。在这项工作中，我们发现背外侧膝状核(DLGN)内的视网膜突触在解剖学和功能上与视网膜突触存在于所有其他视网膜受体区域。因为这些突触对于传递视觉是至关重要的信息传递到大脑皮层，了解它们的形成机制对于恢复皮质下视觉至关重要电路功能。考虑到这一点，本应用程序的目标是识别目标派生的线索负责dLGN中视黄素原性突触的独特发育。初步实验鉴定的胰岛素样生长因子1和富亮氨酸重复序列跨膜神经元蛋白1 (LRRTM1)作为两个突触信号在dLGN中表达。这里将使用分子、遗传学、解剖学和评估这些分子在视网膜生成回路形成中的作用的生理学方法。