Nuclear receptor mechanisms controlling macrophage function in health and disease

控制健康和疾病中巨噬细胞功能的核受体机制

• 批准号: 8448770
• 负责人: Ajay Chawla
• 金额: $ 31.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-20 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448770
• 关键词: Apoptosis; Apoptotic; Applications Grants; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Cell Death; Cells; Cholesterol; Chronic; Coronary Arteriosclerosis; Data; Degenerative Disorder; Development; Disease; Engineering; Ensure; Environment; Gene Expression; Genetic; Goals; Health; Immune Tolerance; Impaired wound healing; Indium; Inflammatory; Injury; Knock-out; Knockout Mice; Laboratories; Lead; Ligands; Link; Macrophage Activation; Metabolism; Methods; Modality; Molecular; Molecular Target; Mus; Muscle; Natural regeneration; Neurons; Nuclear Receptors; Organ; PPAR delta; PPAR gamma; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phagocytes; Phagocytosis; Physiological; Play; Process; Reproduction; Role; Stem cells; Systemic Lupus Erythematosus; Testing; Therapeutic; Tissue Differentiation; Tissue Engineering; Tissues; Work; activating transcription factor; base; cellular targeting; fatty acid metabolism; improved; injury and repair; insight; knockout animal; macrophage; mature animal; mouse model; muscle regeneration; new therapeutic target; novel therapeutics; prevent; programs; receptor; regenerative; residence; response; sensor; tissue regeneration; tissue repair

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：我们的长期目标是了解核受体如何调节健康和疾病中的巨噬细胞基因表达。核受体是调节繁殖，发育和一般代谢的配体激活的转录因子。最近的研究表明，核受体超家族的表达在巨噬细胞激活过程中是动态调节的，表明这些受体在策划巨噬细胞转录反应中起关键作用。实际上，我们实验室和其他实验室的工作表明，过氧化物酶体增殖物激活受体（PPARS）在巨噬细胞胆固醇和脂肪酸代谢中起关键的调节作用，并为冠状动脉疾病中PPAR的心脏保护功能提供了机械基础。尽管巨噬细胞的炎症和致病功能得到了很好的认识，但它们在组织修复和免疫耐受性方面的稳态功能仍然很少了解。我们的初步数据表明，核受体PPAR Delta和Gamma在策划巨噬细胞转录程序中起着关键作用，这是碎片清除和组织再生所必需的。此外，巨噬细胞中这些受体的遗传缺失严重损害了这些稳态反应，从而导致自身免疫或组织修复受损。因此，在本授予申请中提出的研究将采用分子，细胞和遗传方法，包括组织特异性敲除，以进一步研究PPARγ和Delta在损伤和修复过程中如何编排巨噬细胞基因的表达。这些研究的数据将大大增强对巨噬细胞功能在生理和病理生理状况下如何调节的分子理解，并应导致鉴定出新的治疗靶标，以治疗自身免疫性和/或改善损伤后组织再生。 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在巨噬细胞中。