Regulation of Innate Immunity and Inflammation Through Nuclear Reprogramming

通过核重编程调节先天免疫和炎症

• 批准号: 10002161
• 负责人: Jack J Hawiger
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002161
• 关键词: Acute; Acute Disease; Adaptor Signaling Protein; Address; Animals; Apolipoprotein E; Atherosclerosis; Attenuated; Autoimmune Diseases; Bacteria; Binding; Binding Proteins; Biological Assay; Bone Marrow; Cell Nucleus; Cells; Cholesterol; Chronic; Chronic Disease; Development; Disease; Endotoxins; Fatty Acids; Fatty acid glycerol esters; Foam Cells; Gap Junctions; Genetic Transcription; Genome; Glean; Hand; High Fat Diet; Human; Hypersensitivity; Immunity; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Knowledge; Laboratories; Life; Link; Lipids; Lipopolysaccharides; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Methods; Microbe; Mouse Strains; Mus; NF-kappa B; Natural Immunity; Nuclear; Nuclear Import; Nuclear Translocation; Organ; Pathway interactions; Peptides; Play; Population; Pre-Clinical Model; Predisposition; Prevention; Process; Production; Regulation; Regulatory Element; Research Design; Response to stimulus physiology; Role; Signal Pathway; Signal Transduction; Source; Specificity; Sterols; Stimulus; Stress; Triglycerides; Uric Acid; Veterans; Virulence Factors; Virus; Wild Type Mouse; alpha Karyopherins; base; beta Karyopherins; biological adaptation to stress; comparative; design; feeding; fungus; insight; macrophage; microbial; microbial disease; monocyte; mouse model; new therapeutic target; novel therapeutic intervention; nuclear reprogramming; nucleocytoplasmic transport; peripheral blood; public health relevance; response; tool; transcription factor; uptake; wound

 DESCRIPTION: Inflammatory diseases in the Veteran population arise in many ways, ranging from infections, especially of wounds, to metabolic disorders aggravated by stress from tours of duty. Their sequelae range from acute, life-threatening microbial inflammation to chronic and debilitating metabolic inflammation. The body's response to microbial (bacteria, fungi, viruses) and metabolic (excess cholesterol, triglycerides, uric acid) insults is mediated by innate immunity and inflammation. Whatever the source of the stimulus, the response is at first beneficial, but can soon induce harmful inflammatory and metabolic changes in multiple organs. The common nexus of innate immune responses to microbial and metabolic stimuli is intracellular signaling to the nucleus, where the genome is reprogrammed to perpetuate inflammation. However, the interrelation of inflammatory and metabolic signaling in development of disease is poorly understood. We have developed nuclear transport modifiers (NTMs), cell-penetrating peptides designed to inhibit the intracellular nuclear adaptor proteins known as importin alpha 5 (Imp α5) and importin beta 1 (Imp β1) from shuttling both inflammatory and lipid-controlling signals, respectively, to the nucleus. NTMs reduce inflammation by targeting Imp α5-mediated nuclear transport of Stress-Responsive Transcription Factors (SRTFs), exemplified by nuclear factor kappa B, the master regulator of inflammation and immunity. NTMs also inhibit Imp β1-mediated nuclear transport of Sterol Regulatory Element-Binding Protein (SREBP) transcription factors, the master regulators of cholesterol, triglyceride, and fatty acid syntheses and uptake. NTMs have been effective in ameliorating the inflammatory process in relevant preclinical models of microbial, autoimmune, and metabolic diseases. We hypothesize that microbial inflammation is dependent mainly on the Imp α5 pathway whereas metabolic inflammation requires both Imp α5- and Imp β1-mediated pathways. We further hypothesize that cross-talk between the SRTF/Imp α5 and SREBP/Imp β1 signaling pathways predisposes individuals with excessive fat to be more susceptible to microbial insults. We will apply newly designed and produced NTMs as unique probes to independently target Imp α5 or Imp β1 and analyze the two pathways they mediate. We will employ cell-based assays and preclinical models of inflammation induced by a potent proinflammatory microbial virulence factor, bacterial endotoxin, or by a High Fat Diet in atherosclerosis-prone mouse strains. With these unique probes already in hand, Aim 1 will define the role of these two distinct nuclear transport signaling pathways in microbial inflammation, while Aim 2 will define their role in metabolic inflammation. Aim 3 will analyze the comparative roles of SRTF/Imp α5 and SREBP/Imp β1 signaling pathways in development of hypersensitivity to endotoxin in individuals with excessive fat. Cumulatively, our mechanistic studies of nuclear transport will yield much-needed information about innate immune responses to microbial and metabolic insults that are regulated by SRTFs and SREBPs.