Neurotrophic Mechanisms in Retinal Ganglion Cell Maturation

视网膜神经节细胞成熟的神经营养机制

• 批准号: 8136019
• 负责人: Xiaorong Liu
• 金额: $ 32.62万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8136019
• 关键词: Adverse effects; Affect; Aftercare; Age; Amblyopia; Behavior; Birth; Brain; Brain-Derived Neurotrophic Factor; Cell Death; Cell Maturation; Cellular Structures; Characteristics; Childhood; Clinical; Complex; Data; Dendrites; Development; Disease; Exhibits; Eye; Goals; Health; Individual; Knock-out; Length; Molecular; Mono-S; Morphology; Mus; Neurons; Neurotrophin 3; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenocopy; Process; Property; Receptor Protein-Tyrosine Kinases; Research; Research Personnel; Resolution; Retina; Retinal; Retinal Diseases; Retinal Ganglion Cells; Role; Signal Transduction; Structure; Time; Transgenic Mice; Visual; Visual Acuity; Visual impairment; Wild Type Mouse; behavior test; congenital cataract; experience; ganglion cell; infancy; insight; neuron loss; neurotrophic factor; postnatal; prevent; research study; response; vision development

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.

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）在出生后发育过程中如何获得其树突形态。 RGC 复杂而特有的树突结构决定了它们的功能特性。例如，RGC 树突层状模式的形态学特化反映了 ON 和 OFF 通路的功能分离。最近的研究表明，睁眼后，RGC 的树突细化和细化以亚型特异性方式发生，并且这些过程不同地依赖于视觉体验。本提案中的实验将研究 RGC 树突结构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，即脑源性神经营养因子 (BDNF) 和神经营养因子 3 (NT-3)。 BDNF 和 NT-3 通过各自的同源受体酪氨酸激酶 TrkB 和 TrkC 信号传导，已知可调节大脑中神经元的存活、发育和功能。为了研究神经营养蛋白信号传导如何影响 RGC 树突发育，研究人员将使用几种转基因小鼠品系，其中以高分辨率描绘 RGC 结构，并且可以在时间或空间上操纵 BDNF/TrkB 和 NT-3/TrkC 信号传导。研究人员将首先确定睁眼前 RGC 树突结构的发育概况，以及 BDNF/TrkB 和 NT-3/TrkC 信号传导对该过程的确切影响。其次，研究人员将检查 RGC 树突成熟过程中 BDNF/TrkB 和 NT-3/TrkC 信号传导的敏感期，以及神经营养蛋白信号传导改变的影响是否可逆。最后，利用视运动反应的行为测试，研究人员将确定神经营养蛋白敏感的 RGC 成熟如何促进视敏度的正常发育。总之，这些研究将为神经营养素如何影响视网膜回路的建立和完善，以及神经节细胞死亡或异常视觉体验（例如未矫正的先天性白内障和弱视）引起的视网膜疾病的理解和治疗提供有价值的见解。公共健康相关性：我们研究的长期目标是揭示神经营养因子（神经元的生存因子）如何调节出生后视网膜神经节细胞的结构和功能的成熟。这些研究具有重要的临床意义，因为许多视网膜疾病和视力障碍源于婴儿期和儿童期的神经节细胞死亡或神经元连接丧失。我们的研究将为如何使用神经营养素来预防和治疗这些疾病提供新的见解。

项目成果

Retinal Ganglion Cell Loss is Delayed Following Optic Nerve Crush in NLRP3 Knockout Mice.

NLRP3 敲除小鼠视神经受到挤压后，视网膜神经节细胞损失延迟。

• 发表时间: 2016-02-19
• 影响因子: 4.6
• 作者: Puyang, Zhen;Feng, Liang;Chen, Hui;Liang, Peiji;Troy, John B;Liu, Xiaorong
• 通讯作者: Liu, Xiaorong

A laser-induced mouse model of chronic ocular hypertension to characterize visual defects.

激光诱导的慢性高眼压小鼠模型，用于表征视觉缺陷。

• DOI: 10.3791/50440
• 发表时间: 2013-08-14
• 期刊: Journal of visualized experiments : JoVE
• 作者: Liang Feng;Hui Chen;Genn Suyeoka;Xiaorong Liu
• 通讯作者: Xiaorong Liu

Subtype-dependent Morphological and Functional Degeneration of Retinal Ganglion Cells in Mouse Models of Experimental Glaucoma.

实验性青光眼小鼠模型中视网膜神经节细胞的亚型依赖性形态和功能变性。

• DOI: 10.1152/jn.1978.41.2.472
• 发表时间: 2015-05-01
• 期刊: Journal of nature and science
• 作者: Puyang Zhen;Hui Chen;Xiaorong Liu
• 通讯作者: Xiaorong Liu

Multimodal photoacoustic ophthalmoscopy in mouse.

小鼠多模态光声检眼镜。

• 发表时间: 2013-06
• 作者: Song, Wei;Wei, Qing;Feng, Liang;Sarthy, Vijay;Jiao, Shuliang;Liu, Xiaorong;Zhang, Hao F
• 通讯作者: Zhang, Hao F

A lymphatic defect causes ocular hypertension and glaucoma in mice.

淋巴缺陷会导致小鼠高眼压和青光眼。

• DOI: 10.1172/jci77162
• 发表时间: 2014-10-01
• 期刊: The Journal of clinical investigation
• 作者: B. R. Thomson;S. Heinen;M. Jeansson;A. Ghosh;A. Fatima;H. Sung;T. Onay;Hui Chen;Shinji Yamaguchi
• 通讯作者: Shinji Yamaguchi