Genetic Regulation of Macrophage Polarization

描述(申请人提供)：这项研究的长期目标是了解协调巨噬细胞MF极化的基因调控网络。这项提案的一个具体目标是识别和描述决定MFS在不同生理和病理条件下选择性表达哪些基因的“主基因调节因子”。初步研究表明，组蛋白脱乙酰酶Hdac9就是这种调节因子之一。MFS分布于全身，参与炎症过程、组织修复以及先天和获得性免疫反应。朴素的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、往往是相反的调节和功能作用。它们可以显著影响许多疾病的过程，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。另一种激活的MFS，M2，促进组织修复，分泌抗炎或免疫抑制的细胞因子和生长因子。尽管人们对MF极化和极化MFS的功能非常感兴趣，但对于将幼稚MFS激活到M1和M2状态的遗传调控网络的理解仍存在很大差距。我们的中心假设是，存在由一系列离散的转录因子控制的遗传调控网络，这些转录因子促进幼稚或静止的MFS极化到M1和M2状态，并且HDAC9通过促进M2 MFS所需基因的表达，同时抑制M1 MFS中表达的基因，发挥基础作用。本项目将使用一种新型的中频极化蜂窝系统作为实验平台来解决这一中心假设。其具体目的是：1)确认HDAC9在M2表型中上调，并确定哪种HDAC9亚型(S)在M2 MFS中表达；2)实验证实HDAC9调节M2巨噬细胞表型的极化；3)识别HDAC9靶向的基因(上调的M2基因和抑制的M1基因)。实现这些目标将为如何监管MF极化提供重要的见解。这些信息可能会对针对MF在广泛疾病过程中的功能的治疗方法产生重大影响。

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.