STRUCTURE AND FUNCTION RELATIONSHIP OF CONE CYCLIC NUCLEOTIDE-GATED CHANNEL

锥环核苷酸门控通道的结构和功能关系

• 批准号: 8168352
• 负责人: XI-QIN DING
• 金额: $ 26.27万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168352
• 关键词: Accounting; Cessation of life; Color Visions; Complex; Computer Retrieval of Information on Scientific Projects Database; Cyclic GMP; Defect; Disease; Funding; Goals; Grant; Institution; Knockout Mice; Modeling; Molecular; Mus; Mutate; Mutation; Research; Research Personnel; Resources; Retina; Retinal Cone; Retinal Diseases; Role; Source; Structure-Activity Relationship; System; Therapeutic Intervention; United States National Institutes of Health; Visual Acuity; Work; achromatopsia; cyclic-nucleotide gated ion channels; disorder of macula of retina; mouse model; retinal rods

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The cone cyclic nucleotide-gated (CNG) channel is essential for central and color vision and visual acuity. This channel is composed of CNGA3 and CNGB3 subunits. Mutations in cone CNG channel are associated with achromatopsia, progressive cone dystrophy, and some maculopathies; with mutations in CNGB3 alone accounting for 50% of all known cases of achromatopsia. However, our understanding of this channel and related retinopathy is very limited. This is primarily due to the difficulty of investigating the cone system in a rod dominant mammalian retina. We proposed to study cone CNG channel under the normal and mutated conditions using mouse models. Our work shows that the cone dominant Nrl knockout mouse line is a useful model to study cone CNG channel. Using this mouse line we demonstrate that the native cone CNG channel is a heterotetrameric complex comprising both CNGA3 and CNGB3. By using CNGB3 knockout mice, we show the essential role of CNGB3 in cone function and survival. CNGB3 knockout mice show decreased cone function and develop cone degeneration. We also show that the CNGA3-Nrl double knockout mouse line is valuable to study the mechanism of cone degeneration. Using this mouse line we found a drastic accumulation of cGMP in the channel-deficient cones, implicating its role in cone death resulting from CNG channel deficiency. The long-term goal of our research is to elucidate the cellular and molecular mechanism(s) of cone defects in CNG channel deficiency with the objective of identifying potential therapeutic interventions for the cone diseases.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 视锥环核苷酸门控 (CNG) 通道对于中枢视觉、色觉和视力至关重要。 该通道由 CNGA3 和 CNGB3 亚基组成。 视锥细胞 CNG 通道的突变与全色盲、进行性视锥细胞营养不良和一些黄斑病有关；仅 CNGB3 突变就占所有已知全色盲病例的 50%。 然而，我们对这个通道和相关视网膜病变的了解非常有限。 这主要是由于研究视杆细胞占主导地位的哺乳动物视网膜中的视锥细胞系统很困难。 我们建议使用小鼠模型研究正常和突变条件下的锥形 CNG 通道。 我们的工作表明，锥体显性 Nrl 敲除小鼠系是研究锥体 CNG 通道的有用模型。 使用该小鼠系，我们证明天然锥 CNG 通道是包含 CNGA3 和 CNGB3 的异四聚体复合物。 通过使用 CNGB3 敲除小鼠，我们展示了 CNGB3 在视锥细胞功能和生存中的重要作用。 CNGB3 敲除小鼠表现出视锥细胞功能下降并出现视锥细胞变性。 我们还表明 CNGA3-Nrl 双敲除小鼠系对于研究视锥细胞变性机制具有重要价值。 使用该小鼠品系，我们发现 cGMP 在通道缺陷视锥细胞中急剧积累，这表明它在 CNG 通道缺陷导致的视锥细胞死亡中发挥作用。 我们研究的长期目标是阐明 CNG 通道缺陷中视锥细胞缺陷的细胞和分子机制，旨在确定视锥细胞疾病的潜在治疗干预措施。