Targeted Suppression of Cytokine Signaling in the Acute Phase Response

急性期反应中细胞因子信号传导的靶向抑制

• 批准号: 7603048
• 负责人: Jack J Hawiger
• 金额: $ 38.38万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-07 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7603048
• 关键词: Acute; Acute-Phase Proteins; Acute-Phase Reaction; Address; Agonist; Amino Acids; Amyloid Proteins; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Armadillo Repeat; Arteries; Atherosclerosis; Attenuated; Binding; Biological; Biological Markers; Blood; Blood Coagulation Factor; Blood Vessels; Boxing; C-reactive protein; Cardiovascular system; Cell Nucleus; Cells; Cessation of life; Cholesterol; Chronic; Clinical Research; Collaborations; Complement; Coronary Arteriosclerosis; Coronary heart disease; Cues; Cultured Cells; Custom; Cytokine Signaling; Data; Development; Diagnosis; Diet; Dietary Cholesterol; Disease; Disease Progression; Distal; Dominant-Negative Mutation; Dose; Drug or chemical Tissue Distribution; Engineering; Epidemiology; Experimental Models; Family; Family Dasypodidae; Family member; Gene Expression; Genes; Genetic; Genetic Programming; IL6 gene; Importins; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Interleukin-1 beta; Interleukin-6; Investigation; Karyopherins; Laboratories; Link; Lipopolysaccharides; Liver; Low Density Lipoprotein Receptor; Maps; Mediating; Metabolic; Metabolic stress; Methods; Modeling; Molecular; Molecular Weight; Monitor; Morbidity - disease rate; Mus; Mutate; MyD88 protein; Myocardial Infarction; Natural Immunity; Nuclear; Nuclear Import; Organ; Orthologous Gene; Oxidants; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phase; Physiological; Play; Positioning Attribute; Process; Production; Protease Inhibitor; Protein C; Proteins; Publishing; Recombinants; Role; Sepsis; Sepsis Syndrome; Septic Shock; Septicemia; Serum; Serum amyloid A protein; Shock; Signal Pathway; Signal Transduction; Site; Specificity; Spleen; Stress; Stroke; Structure; Study Section; Syndrome; T-Lymphocyte; Tertiary Protein Structure; Testing; Therapeutic; Tissues; Toll-like receptors; Transducers; United States; Variant; Vascular System; Work; adapter protein; age group; alpha Karyopherins; armadillo proteins; attenuation; base; bench to bedside; cellular engineering; chemokine; cytokine; design; feeding; in vivo; indexing; inhibitor/antagonist; innovation; macrophage; meetings; member; microbial; mortality; novel; pathogen; public health relevance; receptor; research study; response; stem; toll-like receptor 4; transcription factor; translational study

DESCRIPTION (provided by applicant): Inflammation, as the major mechanism of disease, underlies vascular system collapse in sepsis ("septic shock") and the development of atherosclerosis. Both disease processes converge prominently in the 60-85 year age group wherein sepsis-related mortality reaches 45%, as compared to a 30% mortality rate encompassing all age groups. Proinflammatory cytokines induce acute phase protein response (APPR). APPR is manifested by the expression of a biomarker, C-reactive protein (CRP), and by elevated levels of serum amyloid proteins, complement proteins, coagulation factors, and protease inhibitors-each contributing to cardiovascular inflammatory injury. CRP and other biomarkers related to the inflammatory process have been the focus of recent epidemiological and clinical studies. Annually, this process underlies 1 million heart attacks, 783,000 strokes, and an estimated 750,000 patients hospitalized with sepsis in the United States. How a high cholesterol Western diet and other microbial and metabolic inducers of inflammation link APPR to atherosclerosis and sepsis awaits elucidation. The central hypothesis of this proposal is that the key intracellular adapter of innate immunity, MyD88, links proinflammatory cues to APPR in sepsis and atherosclerosis. Furthermore, we hypothesize that in response to proinflammatory, oxidant, and metabolic stress, MyD88-mediated signaling induces nuclear import of stress-responsive transcription factors (SRTFs) that are responsible for the genetic reprogramming underlying APPR. To test these two hypotheses, we will use recently-engineered novel cell-penetrating proteins that target MyD88, an adapter protein positioned proximally to Toll-like/IL1/IL18 receptors. To delineate specificity of nuclear import machinery in APPR, we will design, produce, and test cell-penetrating inhibitors to target importin (karyopherin) alpha 1 that shuttles SRTFs to the nucleus. Using animal models that manifest APPR, we will assess the in vivo mechanism of action and therapeutic potential of these cell-penetrating inhibitors. Feasibility for the proposed study is underscored by the applicant's recent advances to suppress the MyD88-STAT1/STAT3- and importin (karyopherin) alpha-mediated signaling pathways using cell-penetrating proteins and peptides. These advances are evidenced by a custom-designed SRTFs nuclear import inhibitor that effectively corrected the aberrant genetic programs for inflammation, apoptosis, tissue injury, and atherosclerosis. Further advances include a recombinant cell penetrating form of SOCS3 that effectively attenuated some of these mechanisms. Results from the proposed investigation will help to harness the potential of cell-penetrating proteins and peptides for use in translational studies, and provide an understanding of the signaling intermediates, crosstalk, and intracellular checkpoints that control APPR. Thus, the proposed studies meet the urgent need for new anti-inflammatory drugs to suppress APPR and its attendant cardiovascular system injury in sepsis and atherosclerosis. PUBLIC HEALTH RELEVANCE: We propose to further develop an innovative form of intracellular protein/peptide therapy to extinguish inflammation and injury to blood vessels in vital organs. Specifically, we will study experimental models of blood poisoning (sepsis) and hardening of arteries (atherosclerosis). Annually, these inflammation-based diseases underlie 1 million heart attacks, 783,000 strokes, and an estimated 750,000 hospitalized sepsis patients in the United States.

描述(申请人提供)：炎症，作为疾病的主要机制，是败血症血管系统崩溃(“败血症休克”)和动脉粥样硬化发展的基础。这两种疾病的过程在60-85岁年龄组明显汇聚，其中与败血症相关的死亡率达到45%，而涵盖所有年龄组的死亡率为30%。促炎细胞因子可诱导急性时相蛋白反应(APPR)。APPR表现为生物标记物C-反应蛋白(CRP)的表达，以及血清淀粉样蛋白、补体蛋白、凝血因子和蛋白酶抑制物水平的升高--每一种都会导致心血管炎症损伤。C反应蛋白和其他与炎症过程相关的生物标志物一直是近年来流行病学和临床研究的重点。每年，在美国，这一过程导致100万人心脏病发作，78.3万人中风，估计有75万名败血症患者住院治疗。高胆固醇的西方饮食和其他微生物和新陈代谢炎症诱导物如何与动脉粥样硬化和脓毒症有关尚待阐明。这一建议的中心假设是，先天免疫的关键细胞内适配器MyD88将促炎症信号与脓毒症和动脉粥样硬化的APPR联系起来。此外，我们假设，在对促炎症、氧化剂和代谢应激的反应中，MyD88介导的信号诱导应激反应转录因子(SRTF)的核输入，这些转录因子负责APPR下的遗传重编程。为了验证这两个假设，我们将使用最近设计的针对MyD88的新型细胞穿透蛋白，MyD88是一种位于Toll样受体/IL1/IL18受体近端的适配蛋白。为了阐明核进口机制在APPR中的特异性，我们将设计、生产和测试靶向Importin(核粘附素)α1的细胞穿透抑制剂，以将SRTF运送到细胞核。使用表现APPR的动物模型，我们将评估这些细胞穿透抑制物的体内作用机制和治疗潜力。申请人最近利用细胞穿透蛋白和多肽抑制MyD88-STAT1/STAT3-和Importin(核粘附素)α介导的信号通路的进展，突显了拟议研究的可行性。一种定制的SRTFS核进口抑制剂有效地纠正了炎症、细胞凋亡、组织损伤和动脉粥样硬化的异常遗传程序，证明了这些进展。进一步的进展包括SOCS3的重组细胞穿透形式，它有效地减弱了其中的一些机制。拟议的研究结果将有助于利用细胞穿透蛋白和多肽用于翻译研究的潜力，并提供对控制APPR的信号中间产物、串扰和细胞内检查点的了解。因此，建议的研究满足了对新的抗炎药物的迫切需要，以抑制脓毒症和动脉粥样硬化中APPR及其伴随的心血管系统损伤。公共卫生相关性：我们建议进一步开发一种创新的细胞内蛋白质/多肽疗法，以消除重要器官中的炎症和血管损伤。具体地说，我们将研究血液中毒(败血症)和动脉硬化(动脉粥样硬化)的实验模型。每年，在美国，这些以炎症为基础的疾病导致100万例心脏病发作、78.3万例中风和大约75万名住院的脓毒症患者。