Melanopsin-dependent light-evoked development of rod photoreceptors

视杆细胞光感受器黑视蛋白依赖性光诱发发育

• 批准号: 10735293
• 负责人: Richard A. Lang
• 金额: $ 40.13万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735293
• 关键词: Adult; Amaze; Apoptosis; Birth; Blood Vessels; Cell Death; Cessation of life; Cone; Data; Dendrites; Development; Developmental Process; Environment; Etiology; Eye; Eye Development; Eye diseases; G alpha q Protein; GTP-Binding Proteins; Glutamate Receptor; Glutamates; Health; Human; Label; Light; Link; Mediating; Mus; Neonatal; Neuromodulator; Pathway interactions; Pattern; Perinatal; Photoreceptors; Process; Public Health; Recording of previous events; Retina; Retinal Ganglion Cells; Retinal Photoreceptors; Rod; Sensory; Structure; Study models; Systems Development; Testing; Time; Traction; Visual; Visual System; Work; dark rearing; design; experience; genetic approach; glutamatergic signaling; interest; intimate behavior; loss of function; melanopsin; novel; organ growth; postnatal; precursor cell; prevent; progenitor; response; retinal neuron; retinal rods; sensor; single cell analysis; single cell sequencing; vision development

It has been known for some time that development of the visual system can be an adaptive process in which light exposure or visual experience modifies the final structure. Here we propose to investigate a developmental pathway in which photoreception via OPN4 in intrinsically photosensitive retinal ganglion cells (ipRGCs) regulates rod photoreceptor survival. Preliminary data show that light and OPN4 regulate rod precursor cell death in the neonatal retina and rod number in adult mice. This is mediated by the neuromodulator glutamate. We suggest that ipRGC outer retinal dendrites (ORDs) deliver glutamate to the outer retina and regulate rod survival. ORDs are unique to ipRGCs and are transient, existing only during the first week after birth. Single cell sequencing data reveal that the glutamate receptor Grik3 is expressed in rod precursors transiently in the first week after birth and is thus a good candidate to mediate this response. These data suggest the Central Hypothesis that Perinatal light sensing by ipRGCs regulates rod photoreceptor number via glutamate-induced precursor cell death. We propose three Aims designed to define the mechanisms underlying this proposed adaptive response. We will define the developmental time-course of ORDs and assess markers of glutamate function (Aim 1), assess the proposed relationships in the light-OPN4-Gαq-rod cell death pathway (Aim 2), and assess glutamate delivery by ipRGC ORDs and the response of rod precursors (Aim 3). The finding that early developmental light sensing regulates the number of rod photoreceptors is unexpected and of broad interest because it represents a novel mechanism and has implications for human eye development.

一段时间以来，人们已经知道，视觉系统的发展可以是一种适应性的， 曝光或视觉体验改变最终结构的过程。这里我们 我建议研究一种发育途径，在这种途径中， 视网膜内光敏神经节细胞（ipRGC）调节视杆细胞 生存初步数据表明，光和OPN 4调节视杆细胞前体细胞死亡， 成年小鼠的新生视网膜和视杆数。这是由神经调节剂谷氨酸介导的。 我们认为ipRGC外视网膜树突（ORD）将谷氨酸递送到外视网膜， 调节杆的存活。ORD是ipRGC所特有的，并且是短暂的，仅在第一次治疗期间存在。 出生后一周。单细胞测序数据显示，谷氨酸受体Grik 3表达于 在出生后的第一周内，杆前体细胞中存在短暂的表达，因此是一个很好的候选者， 这个回应。这些数据表明，中央假说，围产期光感应， ipRGC通过谷氨酸诱导的前体细胞死亡调节视杆细胞数量 我们提出了三个目标，旨在定义这种自适应的机制 反应我们将定义ORD的发展时间进程并评估标志物 谷氨酸功能（目的1），评估光-OPN 4-Gα q-杆细胞中的拟议关系 死亡途径（目的2），并通过ipRGC ORD和视杆细胞反应评估谷氨酸递送 前体（目标3）。早期发育的光感调节了 的杆状光感受器是意想不到的，并广泛的兴趣，因为它代表了一种新的 这一机制对人类眼睛的发育具有重要意义。