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.

摘要： 敲除编码烟碱-7乙酰胆碱受体（nAChR）的基因， 确定了β 7 nAChR是抗炎活性的绝对要求， 迷走神经然而，在人类中，存在一种自然发生的人类特异性机制， 它模拟了β 7 nAChR的基因敲除。在此过程中，人类特异性基因CHRFAM 7A 是一个显性负性抑制剂的β 7 nAchR。因为CHRFAM 7表达从最多到 200倍之间的个体，它是理想的适合衡量抗炎活性的 人类迷走神经在此，我们假设人CHRFAM 7A的转基因表达 小鼠中的α 7 nAchR基因将导致与α 7 nAchR敲除小鼠相似的表型，并导致 基于CHRFAM 7A的表达的功能性“人表型”。为此，我们将（1） 确定单核细胞/巨噬细胞中CHRFAM 7A表达的生物学后果 （2）表征CHRFAM 7A表达对原发性肝癌中α 7 nAchR信号传导的影响。 人巨噬细胞和（3）比较引入 将CHRFAM 7A基因导入小鼠。在本研究项目结束时，我们将（1）建立 CHRFAM 7A对α 7 nAchR炎症信号传导的生物学意义，（2） 确定体内CHRFAM 7A表达的结果，和（3）确定是否 CHRFAM 7A具有改变迷走神经信号传导的抗炎作用的能力。