CHOLINE TRANSPORTERS SPECIFICALLY TARGET NON-NEURONAL ACETYLCHOLINE SYNTHESIS

胆碱转运蛋白专门针对非神经元乙酰胆碱合成

• 批准号: 7716003
• 负责人: Pill-Soon Song
• 金额: $ 2.77万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7716003
• 关键词: Acetylcholine; Asthma; Cell Proliferation; Cells; Choline; Cholinergic Agents; Class; Computer Retrieval of Information on Scientific Projects Database; Coupled; Data; Epithelial Cells; Funding; Grant; Institution; Link; Lung; Lung diseases; Malignant Epithelial Cell; Malignant neoplasm of lung; Mediating; Modeling; Neuroendocrine Cell; Neuroglia; Neurons; Play; Proteins; Rate; Research; Research Personnel; Resources; Role; Signal Transduction; Sodium; Source; Squamous Cell Lung Carcinoma; Testing; United States National Institutes of Health; choline transporter; cholinergic; knock-down; lung Carcinoma; uptake

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. Non-neuronal acetylcholine (Ach) synthesis and secretion may play a role in lung diseases such as lung cancer and asthma. In order to characterize and target non-neuronal signaling in lung it is necessary to identify a step that differs between neuronal and non-neuronal cholinergic signaling. Choline uptake is a rate-limiting step for ACh synthesis and may provide this target. In neurons, the sodium-dependent, high-affinity choline transporter (CHT1) is absolutely required to transport choline into neurons for ACh synthesis. Our preliminary data shows that CHT1 is not required by some lung cells for ACh synthesis and that instead a newly described class of choline transporters, the choline transporter-like proteins (CTL1 - 5), can mediate ACh synthesis. Therefore non-neuronal ACh synthesis in lung may potentially be targeted without effecting neuronal ACh synthesis by targeting the correct CTL. To test this we propose the following specific aims: (1) Identification of which choline transporter-like proteins are involved in choline-uptake in lung non-neuronal cells. (2) Identification of which CTL is coupled to non-neuronal ACh synthesis in lung. (3) To determine if knockdown of the CTL linked to ACh synthesis can block lung cell proliferation. These aims will be implemented using specific siRNAs to knock down CTLs in H82 small cell lung carcinoma cells as a model for pulmonary neuroendocrine cells and H520 squamous cell lung carcinoma cells as a model for airway epithelial cells. These studies will thus allow the targeting of non-neuronal ACh synthesis as a first step in developing new therapies for lung diseases.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 非神经元乙酰胆碱（ACH）合成和分泌可能在肺癌和哮喘等肺部疾病中起作用。 为了表征和靶向肺中的非神经元信号传导，有必要确定神经元和非神经元胆碱能信号之间不同的步骤。胆碱摄取是ACH合成的限速步骤，并可能提供此目标。在神经元中，绝对需要依赖钠的高亲和力胆碱转运蛋白（CHT1）才能将胆碱转运到神经元中以进行ACH合成。我们的初步数据表明，某些肺细胞不需要CHT1进行ACH合成，而是新描述的胆碱转运蛋白类别，胆碱转运蛋白样蛋白（CTL1-5）可以介导ACH合成。 因此，肺中的非神经元ACH合成可能是可能被靶向的，而无需通过靶向正确的CTL来影响神经元ACH合成。 为了测试这一点，我们提出以下特定目的：（1）鉴定哪些胆碱转运蛋白样蛋白参与肺非神经元细胞中的胆碱摄取。 （2）识别哪些CTL与肺中的非神经元ACH合成偶联。 （3）确定与ACH合成相关的CTL的敲低是否可以阻止肺部细胞增殖。这些目标将使用特定的siRNA实施，以将H82小细胞肺癌细胞中的CTL击倒，作为肺神经内分泌细胞和H520鳞状细胞肺癌细胞的模型，作为气道上皮细胞的模型。因此，这些研究将允许将非神经元ACH合成作为开发肺部疾病新疗法的第一步。