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.
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.
