Our long-term goal is to understand how nuclear receptors regulate macrophage gene expression in health and disease. Nuclear receptors are ligand-activated transcription factors that modulate reproduction, development, and general metabolism. Recent studies indicate that expression of nuclear receptor superfamily is dynamically modulated during macrophage activation, indicating that these receptors play a pivotal role in orchestrating macrophage transcriptional responses. Indeed, work from our laboratory and those of others has shown that Peroxisome Proliferator Activated Receptors (PPARs) play a key regulatory role in macrophage cholesterol and fatty acid metabolism, and has provided the mechanistic basis for the cardioprotective functions of PPARs in coronary artery disease. While the inflammatory and pathogenic functions of macrophages are well appreciated, their homeostatic functions in tissue repair and immune tolerance remain poorly understood. Our preliminary data indicate the nuclear receptors PPAR delta and gamma play a key role in orchestrating macrophage transcriptional programs necessary for debris clearance and tissue regeneration. Moreover, genetic deletion of these receptors in macrophages severely compromises these homeostatic responses, leading to autoimmunity or impaired tissue repair. Therefore, studies proposed in the present grant application will take molecular, cellular, and genetic approaches, including tissue-specific knockouts, to further investigate how PPAR gamma and delta orchestrate macrophage gene expression during injury and repair. Data from these studies will greatly enhance the molecular understanding of how macrophage functions are regulated under physiologic and pathophysiologic conditions, and should lead to identification of new therapeutic targets for treating autoimmunity and/or improving tissue regeneration after injury.
The specific aims of this proposal are to: 1) Determine the molecular mechanisms by which macrophage-specific PPAR delta and gamma control tolerogenic responses, 2) Investigate the regulatory role of macrophage-specific PPAR delta and gamma in tissue regeneration and repair, and 3) Generate macrophage-specific PPAR delta/gamma double knockout mice to elucidate their non-redundant functions in macrophages.
Macrophages take residence in almost all organs of the body, where they guard against damage and perform tissue repairs. Studies in this grant application will explore the role of nuclear receptors in controlling these reparative programs of macrophages. Insights from these studies should lead to development of new therapeutics to treat chronic inflammatory and degenerative diseases, and improve modalities for tissue regeneration.
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|Odegaard, Justin I; Chawla, Ajay (2013) Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science 339:172-7|
|Eisele, Nicholas A; Ruby, Thomas; Jacobson, Amanda et al. (2013) Salmonella require the fatty acid regulator PPARýý for the establishment of a metabolic environment essential for long-term persistence. Cell Host Microbe 14:171-82|
|Heredia, Jose E; Mukundan, Lata; Chen, Francis M et al. (2013) Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration. Cell 153:376-88|
|Wynn, Thomas A; Chawla, Ajay; Pollard, Jeffrey W (2013) Macrophage biology in development, homeostasis and disease. Nature 496:445-55|
|Chao, Lily C; Soto, Erin; Hong, Cynthia et al. (2013) Bone marrow NR4A expression is not a dominant factor in the development of atherosclerosis or macrophage polarization in mice. J Lipid Res 54:806-15|
|Odegaard, Justin I; Chawla, Ajay (2011) Alternative macrophage activation and metabolism. Annu Rev Pathol 6:275-97|
|Wu, Davina; Molofsky, Ari B; Liang, Hong-Erh et al. (2011) Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332:243-7|
|Dunn, Shannon E; Bhat, Roopa; Straus, Daniel S et al. (2010) Peroxisome proliferator-activated receptor delta limits the expansion of pathogenic Th cells during central nervous system autoimmunity. J Exp Med 207:1599-608|
|Chawla, Ajay (2010) Control of macrophage activation and function by PPARs. Circ Res 106:1559-69|
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