Biogenesis of IL-1a in inflammatory process

IL-1a 在炎症过程中的生物发生

• 批准号: 9302264
• 负责人: Dmitry Shayakhmetov
• 金额: $ 23.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-21 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302264
• 关键词: Acute; Affect; Applications Grants; Autoimmune Process; Automobile Driving; Binding; Biogenesis; Biological; Biological Process; Biology; CASP1 gene; CASP8 gene; Cardiovascular Diseases; Cell membrane; Cells; Chronic; Diabetes Mellitus; Disease; Event; Exhibits; Goals; Health; Hematopoietic; Homeostasis; Host Defense; Human; Human Pathology; Immune response; In Vitro; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 alpha; Interleukin-1 beta; Intervention; Kinetics; Lead; Ligands; Link; Maintenance; Malignant Neoplasms; Mediator of activation protein; Membrane; Modeling; Modification; Molecular; Molecular Models; Necrosis; Normal tissue morphology; Obesity; Organ; Pathogenesis; Pathologic; Pathology; Pharmacology; Physiological; Post-Translational Protein Processing; Process; Production; Proteins; Proteolytic Processing; Pyrogens; Recruitment Activity; Role; Signal Transduction; Site; Sterility; Stimulus; Stress; Viral; autoinflammatory; base; cytokine; cytotoxic; feeding; human disease; in vitro activity; in vivo; insight; interleukin-1 receptor type I; molecular modeling; new therapeutic target; novel; pathogen; public health relevance; receptor; response; therapeutic target

ABSTRACT IL-1/IL-1RI signaling is pivotal for driving dysregulation of homeostasis in normal tissues through inflammation, a process of recruitment and retention of specialized cells of hematopoietic origin, which may and often does lead to the disruption of physiological function of the affected organ. Today, the pathogenesis of the vast majority of human diseases has been linked to the acute or chronic inflammation as the key components of homeostatic dysregulation, mechanistically underlying numerous and specific disease-driving pathologies. IL- 1RI signaling is initiated upon binding of either of two principal non-homologous ligands of the receptor – IL-1α or IL-1β. Over the past decade, truly remarkable progress has been made in understanding the biology of IL-1β due to the discovery of the caspase-1-dependent inflammasome(s) and caspase-8 as regulators of IL-1β biogenesis. In stark contrast to IL-1β, and despite being the first major human pyrogen described (Dinarello et al., 1974), the biogenesis of IL-1α remains poorly understood. Furthermore, despite increasing appreciation of the contribution of IL-1α in the pathogenesis of many important human diseases, the factors that control functional IL-1α maturation remain completely obscure. The goal of this exploratory grant proposal is to identify specific molecular modifications of IL-1α precursor that enable physiological IL-1α function in its membrane- bound and secreted forms. In Specific Aim 1, we will define the functional role of specific post-translational modifications of pro-IL-1α for eliciting IL-1α biological activity as secreted and membrane-bound cytokines in vitro. In Specific Aim 2, we will define molecular forms of IL-1α, triggering inflammatory IL-1RI signaling in response to viral and bacterial pathogens and cytotoxic injury in vivo. These studies should aid in developing a unifying conceptual model of biogenesis of IL-1α that enables protective and pathologic IL-1α-driven host responses to pathogens, stress, and sterile injury. These studies have the potential to shift the currently- accepted IL-1β-centric paradigm of inflammation to a concept of IL-1α-dependent pro-inflammatory priming at a site of injury or infection as the initiator and sustainer of inflammation underlying a great number of human diseases.

抽象的 IL-1/IL-1RI信号传导是通过注射来驱动正常组织中稳态失调的关键， 招募和保留造血起源的专业细胞的过程，这可能也经常这样做 导致受影响器官的身体功能破坏。今天，疫苗的发病机理 大多数人类疾病已与急性或慢性感染有关 稳态失调，机械上的基础是许多驱动疾病的病理。 il- 1RI信号传导是在受体的两个主要非同源配体中的两种主体配体的结合时启动的。IL-1α 或IL-1β。在过去的十年中，在理解IL-1β的生物学方面取得了真正的进步 由于发现caspase-1依赖性炎症体（S）和caspase-8作为IL-1β的调节剂 生物发生。与IL-1β形成鲜明对比的是，涂料是描述的第一个主要人类热原（Dinarello et Al。，1974），IL-1α的生物发生知之甚少。此外，dospite对 IL-1α在许多重要人类疾病的发病机理中的贡献，这些因素控制 功能性IL-1α成熟仍然完全晦涩。该探索性赠款建议的目标是确定 IL-1α前体的特定分子修饰，使物理IL-1α在其膜中的功能 绑定和分泌的形式。在特定目标1中，我们将定义特定翻译后的功能作用 Pro-IL-1α的修饰，以引发IL-1α生物学活性，作为分泌和膜结合的细胞因子 体外。在特定的目标2中，我们将定义IL-1α的分子形式，从而触发炎症IL-1RI信号传导 对病毒和细菌病原体以及体内细胞毒性损伤的反应。这些研究应有助于开发 IL-1α的生物发生的统一概念模型，该模型能够受保护和病理IL-1α驱动的宿主 对病原体，压力和无菌损伤的反应。这些研究有可能改变当前的 - 接受的以IL-1β为中心的炎症范例，依赖于IL-1α依赖性促炎性启动的概念 受伤或感染的部位是大量人类的引发者和维持感染者 疾病。