The Human-Specific Gene CHRFAM7A in Leukocytes

白细胞中的人类特异性基因 CHRFAM7A

• 批准号: 9214186
• 负责人: Todd W Costantini
• 金额: $ 31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9214186
• 关键词: Adhesions; Animal Model; Anti-Cholinergics; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Biological; Cell Adhesion; Cell Line; Cell Proliferation; Cell surface; Cells; Cholinergic Receptors; D Cells; Data; Dominant-Negative Mutation; Gene Proteins; Genes; Goals; Human; Human Activities; Human Genome; Immune; Immune response; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Knock-out; Knockout Mice; Leukocytes; Macrophage Activation; Measures; Mediating; Messenger RNA; Molecular Chaperones; Mus; Nicotinic Receptors; Phenotype; Positioning Attribute; Process; Proteins; Rattus; Research Project Grants; Severities; Signal Transduction; Structure of thyroid parafollicular cell; Therapeutic; Transfection; Transgenic Mice; Transgenic Organisms; Translations; Vagus nerve structure; Variant; alpha-bungarotoxin receptor; base; cell motility; cholinergic; in vivo; inhibitor/antagonist; insight; knock-down; macrophage; migration; monocyte; mouse genome; neurotransmission; overexpression; protein expression; response; response to injury; transgene expression; vagus nerve stimulation

Abstract: Knock out of the gene encoding the -7 nicotinic acetylcholine receptor (7nAChR) has established that 7nAChR is an absolute requirement for the anti-inflammatory activity of the vagus nerve. In humans however, there exists a naturally occurring human-specific mechanism that mimics gene knock down of 7nAChR. In this process, the human specific gene CHRFAM7A is a dominant negative inhibitor of 7nAchR. Because CHRFAM7 expression varies from up to 200 fold between individuals, it is ideally suited to gauge the anti-inflammatory activity of the human vagus nerve. Here we hypothesize that transgenic expression of the human CHRFAM7A gene in mouse will lead to a phenotype similar to the α7nAchR knockout mouse and result in a functional “human phenotype” based on the expression of CHRFAM7A. To this end, we will (1) determine the biological consequence of CHRFAM7A expression in monocytes/macrophage cell lines, (2) characterize the effects of CHRFAM7A expression on α7nAchR signaling in primary human macrophages and (3) compare the biological consequences of introducing the CHRFAM7A gene into mice. At the conclusion of this research project we will have (1) established the biological significance of CHRFAM7A to inflammatory signaling by the α7nAchR, (2) determined the consequence of CHRFAM7A expression in vivo, and (3) established whether CHRFAM7A has the ability to alter the anti-inflammatory effects of vagus nerve signaling.

抽象的： 敲除编码 α-7 烟碱乙酰胆碱受体 (α7nAChR) 的基因 确定 α7nAChR 是其抗炎活性的绝对必要条件 然而，在人类中，存在一种自然发生的人类特异性机制。 模拟 7nAChR 的基因敲除，在此过程中，人类特有的基因 CHRFAM7A 被敲除。 是 α7nAchR 的显性失活抑制剂，因为 CHRFAM7 的表达变化范围为 个体之间的差异为 200 倍，非常适合测量 在这里，我们捕获了人类 CHRFAM7A 的转基因表达。 小鼠体内的基因将导致与 α7nAchR 敲除小鼠相似的表型，并导致 基于 CHRFAM7A 表达的功能性“人类表型” 为此，我们将 (1) 确定单核细胞/巨噬细胞中 CHRFAM7A 表达的生物学后果 线，（2）表征原代细胞中 CHRFAM7A 表达对 α7nAchR 信号传导的影响 人类巨噬细胞和（3）比较引入 在本研究项目结束时，我们将 (1) 建立小鼠体内的 CHRFAM7A 基因。 CHRFAM7A 对 α7nAchR 炎症信号传导的生物学意义，(2) 确定 CHRFAM7A 体内表达的结果，以及 (3) 是否成立 CHRFAM7A 能够改变迷走神经信号的抗炎作用。