The Human-Specific Gene CHRFAM7A in Leukocytes

摘要： 敲除了编码-7烟碱型乙酰胆碱受体(7nAChR)的基因 确定7nAChR是抗炎活性的绝对要求 迷走神经。然而，在人类身上，存在一种自然发生的人类特有的机制。 模拟7nAChR基因敲除。在这个过程中，人类特有的基因CHRFAM7A 是7nAchR的主要负性抑制因子。因为CHRFAM7的表达从最多到 200倍的个体之间，它是理想的适合于衡量抗炎活性的 人类迷走神经。在这里，我们假设人CHRFAM7A的转基因表达 小鼠的基因将导致类似于α7nAchR基因敲除小鼠的表型，并导致 基于CHRFAM7A表达的功能性“人类表型”。为此，我们将(1) 确定CHRFAM7A在单核/巨噬细胞中表达的生物学后果 品系，(2)CHRFAM7A表达对原代α7nAchR信号的影响 人类巨噬细胞和(3)比较了引入 CHRFAM7A基因导入小鼠。在本研究项目结束时，我们将建立(1) CHRFAM7A在α7nAchR炎症信号转导中的生物学意义(2) 确定CHRFAM7A在体内表达的后果，以及(3)确定 CHRFAM7A具有改变迷走神经信号的抗炎作用的能力。

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.