The Human-Specific Gene CHRFAM7A in Leukocytes

白细胞中的人类特异性基因 CHRFAM7A

• 批准号: 9897415
• 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/9897415
• 关键词: Adhesions; Animal Model; Anti-Cholinergics; Anti-Inflammatory Agents; Antiinflammatory Effect; 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; severe 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： 从编码-7的烟碱乙酰胆碱受体（7NACHR）的基因中敲出具有 确定7NACHR是对抗炎活性的绝对要求 迷走神经。然而，在人类中，存在一种天然存在的人类特异性机制 那种模仿基因击倒7nachr。在此过程中，人类特异性基因chrfam7a 是7NACHR的主要负抑制剂。因为Chrfam7表达式从最多到 个人之间200倍，理想情况下是适合评估抗炎活性的 人迷走神经。在这里，我们假设人类Chrfam7a的转基因表达 小鼠中的基因将导致类似于α7NACHR敲除小鼠的表型，并导致A 基于CHRFAM7A的表达的功能“人类表型”。为此，我们将（1） 确定单核细胞/巨噬细胞中CHRFAM7A表达的生物学结果 线，（2）表征了Chrfam7a表达对原发性α7NACHR信号传导的影响 人类巨噬细胞和（3）比较引入的生物学后果 CHRFAM7A基因进入小鼠。在该研究项目的结尾，我们将建立（1） CHRFAM7A对α7NACHR炎症信号传导的生物学性，（2） 确定体内Chrfam7a表达的后果，（3）确定是否是否 CHRFAM7A具有改变迷走神经信号传导的抗炎作用的能力。