Genetic Regulation of Macrophage Polarization

描述（由申请人提供）：本研究的长期目标是了解协调巨噬细胞Mf极化的遗传调控网络。在这个建议的一个具体目标是确定和表征“主遗传调节因子”，确定哪些基因在不同的生理和病理条件下选择性表达的MFS。初步研究表明，一种这样的调节剂是组蛋白脱乙酰酶，Hdac9。Mfs位于全身各处，参与炎症过程、组织修复以及先天性和适应性免疫反应。幼稚Mfs可以被激活或极化到不同的功能状态，这些状态在炎症中具有不同的且通常相反的调节和功能作用。它们可以显著影响许多疾病过程，包括传染病、自身免疫性疾病和癌症。经典激活的Mfs，M1，是吞噬细胞，分泌促炎介质，促进病原体破坏和清除。或者激活Mfs、M2，促进组织修复并分泌抗炎或免疫抑制的细胞因子和生长因子。尽管对Mf极化和极化Mfs的功能有着浓厚的兴趣，但对调节幼稚Mfs活化为M1和M2状态的遗传调控网络的理解存在很大的差距。我们的中心假设是，有一个离散级联的转录因子，促进极化的幼稚或'休息' MFS的M1和M2状态和HDAC9起着重要的作用，促进M2 MFS所需的基因的表达，同时抑制基因表达M1 MFS的基因控制的遗传调控网络。该项目将使用一种新的MF极化细胞系统作为实验平台来解决这个中心假设。具体目标是：1）证实HDAC 9在M2表型中的上调并确定哪种HDAC 9同种型在M2 Mfs中表达，2）通过实验证实HDAC 9调节M2巨噬细胞表型的极化和3）鉴定HDAC 9靶向的基因（上调的M2基因和抑制的M1基因）。实现这些目标将提供重要的见解如何Mf极化的调节。这一信息可能对靶向广泛疾病过程中Mf功能的治疗方法产生重大影响。 公共卫生相关性：巨噬细胞是免疫系统的关键细胞，在不同的生理和病理条件下发挥许多不同的功能。该项目将通过表征关键调节蛋白HDAC9的作用来确定调节巨噬细胞功能的遗传机制，HDAC9可能在调节巨噬细胞反应中起主要作用。了解这个和其他调节巨噬细胞功能的因素的作用应该提供新的和新颖的方法来理解和靶向巨噬细胞在各种疾病过程中的功能。

DESCRIPTION (provided by applicant): The long term objective of this research is to understand the genetic regulatory networks that orchestrate macrophage Mf polarization. A specific goal in this proposal is to identify and characterize 'master genetic regulators' that determine which genes are selectively expressed by Mfs in different physiological and pathologic conditions. Preliminary studies suggest that one such regulator is a histone deacetylase, Hdac9. Mfs are located throughout the body and are involved in inflammatory processes, tissue repair and innate and adaptive immune responses. Naive Mfs can be activated or polarized to different functional states that have distinct and often opposing regulatory and functional roles in inflammation. They can significantly influence many disease processes, including infectious disease, autoimmune disease and cancer. Classically activated Mfs, M1, are phagocytic, secrete pro-inflammatory mediators and promote pathogen destruction and clearance. Alternatively activated Mfs, M2, promote tissue repair and secrete cytokines and growth factors that are anti-inflammatory or immunosuppressive. Despite intense interest in Mf polarization and the functions of polarized Mfs, there is a large gap in the understanding of the genetic regulatory networks that regulate the activation of naive Mfs into M1and M2 states. Our central hypotheses is that there are genetic regulatory networks controlled by a discrete cascade of transcription factors that promote polarization of naive or 'resting' Mfs to M1 and M2 states and that HDAC9 plays a fundamental role by promoting expression of genes required by M2 Mfs while simultaneously repressing genes expressed in M1 Mfs. This project will use a novel cellular system of Mf polarization as an experimental platform to address this central hypothesis. The specific aims are to: 1) confirm upregulation of HDAC 9 in the M2 phenotype and determine which HDAC9 isoform(s) is(are) expressed in M2 Mfs, 2) confirm experimentally that HDAC9 regulates polarization of the M2 macrophage phenotype and 3) identify genes targeted by HDAC9 (M2 genes that are upregulated and M1 genes that are suppressed). Achieving these goals will provide important insights on how Mf polarization is regulated. This information could have a significant impact on therapeutic approaches that would target Mf functions in a wide range of disease processes. PUBLIC HEALTH RELEVANCE: Macrophages are key cells of the immune system and serve many different functions under differing physiologic and pathologic conditions. This project will identify genetic mechanisms that regulate how macrophages function by characterizing the role of a key regulatory protein, HDAC9, that may have a major role in regulating macrophage responses. Understanding the role of this and other factors that regulate macrophage functions should provide new and novel approaches to understanding and targeting macrophage functions in a wide variety of disease processes.