Neurotrophic Mechanisms in Retinal Ganglion Cell Maturation

描述（由申请人提供）：拟议研究的目标是揭示视网膜神经节细胞（RGC）如何在出生后发育过程中获得其树突状形态。RGC复杂而独特的树突状结构决定了它们的功能特性。例如，RGC树突的层状模式中的形态专业化反映了ON和OFF途径的功能分离。最近的研究表明，视网膜神经节细胞的树突状加工和细化在睁眼后以亚型特异性的方式发生，并且这些过程不同地依赖于视觉体验。本实验将探讨RGC树突状结构在出生后发育的分子机制。具体来说，研究人员将重点关注两种神经营养因子的作用，脑源性神经营养因子（BDNF）和神经营养因子3（NT-3）。已知BDNF和NT-3通过其各自的同源受体酪氨酸激酶TrkB和TrkC进行信号传导以调节脑中神经元的存活、发育和功能。为了研究神经营养因子信号如何影响RGC树突发育，研究人员将使用几种转基因小鼠，其中RGC结构以高分辨率描绘，BDNF/TrkB和NT-3/TrkC信号可以在时间或空间上进行操纵。研究人员将首先确定RGC树突状结构在睁眼前的发育概况，以及BDNF/TrkB和NT-3/TrkC信号传导对这一过程的确切影响。其次，研究人员将检查BDNF/TrkB和NT-3/TrkC信号在RGC树突成熟中的敏感期，以及改变的神经营养因子信号的影响是否可逆。最后，使用视运动反应的行为测试，研究者将确定神经营养因子敏感的RGC成熟如何有助于视力的正常发育。总之，这些研究将为神经营养因子如何影响视网膜回路的建立和完善，以及对神经节细胞死亡或异常视觉体验（如未矫正的先天性白内障和弱视）导致的视网膜疾病的理解和治疗提供有价值的见解。公共卫生相关性：本研究的长期目标是揭示神经营养因子，神经元的存活因子，如何调节出生后视网膜神经节细胞结构和功能的成熟。这些研究具有重要的临床意义，因为许多视网膜疾病和视觉障碍起源于婴儿和儿童时期的神经节细胞死亡或神经元连接丧失。我们的研究将为神经营养因子如何用于预防和治疗这些疾病提供新的见解。

DESCRIPTION (provided by applicant): The goal of the proposed study is to reveal how retinal ganglion cells (RGCs) acquire their dendritic morphology during postnatal development. The complex yet characteristic dendritic structure of RGCs governs their functional properties. For example, morphological specialization in the laminar patterns of RGC dendrites reflects the functional separation of ON and OFF pathways. Recent studies have revealed that dendritic elaboration and refinement of RGCs take place in a subtype-specific manner after eye- opening and that these processes depend differently on visual experience. Experiments in this proposal will study the molecular mechanisms underlying the postnatal development of RGC dendritic structure. Specifically, the investigators will focus on the roles of two neurotrophins, Brain-derived neurotrophic factor (BDNF) and Neurotrophin 3 (NT-3). BDNF and NT-3 signaling through their respective cognate receptor tyrosine kinases, TrkB and TrkC, are known to regulate the survival, development, and function of neurons in the brain. To study how neurotrophin signaling affects RGC dendritic development, the investigators will use several lines of transgenic mice in which RGC structures are delineated in high resolution and BDNF/TrkB and NT-3/TrkC signaling can be manipulated temporally or spatially. The investigators will first determine the developmental profile of RGC dendritic structure before eye-opening and the exact effects of BDNF/TrkB and NT-3/TrkC signaling on this process. Second, the investigators will examine the sensitive periods of BDNF/TrkB and NT-3/TrkC signaling in RGC dendritic maturation and whether the effects of altered neurotrophin signaling are reversible. Finally, using a behavioral test of optomotor responses, the investigators will determine how the neurotrophin-sensitive RGC maturation contributes to the normal development of visual acuity. Together, these studies will provide valuable insights on how neurotrophins affect the establishment and refinement of retinal circuitry, and on the understanding and treatment of retinal disorders resulting from ganglion cell death or abnormal visual experiences, such as uncorrected congenital cataracts and amblyopia. PUBLIC HEALTH RELEVANCE: The long-term goal of our research is to reveal how neurotrophins, the survival factors for neurons, modulate the maturation of structure and function of retinal ganglion cells after birth. These studies are of great clinical importance, because many retinal disorders and visual impairments originate from ganglion cell death or loss of neuronal connectivity during infancy and childhood. Our studies will provide new insights on how neurotrophins could be used to prevent and treat these diseases.