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.

摘要 IL-1/IL-1RI信号通路通过炎症作用推动正常组织内环境平衡失调。 一种募集和保留来自造血细胞的特殊细胞的过程，这可能而且经常是这样做的 导致受影响器官的生理功能中断。今天，病机浩瀚 大多数人类疾病都与急性或慢性炎症有关，因为它们是 动态平衡失调，是许多特定的疾病驱动病理的机械基础。伊尔- 1RI信号是在受体的两个主要非同源配体-IL-1α结合时启动的 或IL-1β。在过去的十年里，在了解IL-1β的生物学方面取得了真正显著的进展 由于发现了caspase-1依赖的炎症体(S)和caspase-8作为IL-1β的调节因子 生物发生学。与IL-1β形成鲜明对比的是，尽管是第一个被描述的主要人类热原(Dinarello et 等人，1974年)，IL-1α的生物发生仍然知之甚少。此外，尽管对 IL-1α在许多重要人类疾病发病机制中的作用及其控制因素 功能性IL-1α的成熟仍然完全不清楚。这项探索性拨款提案的目标是确定 IL-1α前体的特异性分子修饰使其膜上的IL-1α具有生理功能- 捆绑的和秘密的形式。在具体目标1中，我们将定义特定翻译后的功能作用 修饰前IL-1α诱导IL-1α作为分泌型和膜结合型细胞因子的生物学活性 体外培养。在特定目标2中，我们将定义IL-1α的分子形式，在体内触发炎症IL-1RI信号 对病毒和细菌病原体以及体内细胞毒性损伤的反应。这些研究应该有助于开发一种 IL-1α生物发生的统一概念模型，支持保护性和病理性IL-1α驱动的宿主 对病原体、压力和无菌伤害的反应。这些研究有可能改变目前- 被接受的以IL-1β为中心的炎症范式到IL-1α依赖的促炎启动的概念 作为炎症的起始者和持续者的受伤或感染的部位，在大量人类 疾病。