Biogenesis of IL-1a in inflammatory process

IL-1a 在炎症过程中的生物发生

• 批准号: 9195213
• 负责人: Dmitry Shayakhmetov
• 金额: $ 19.5万
• 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/9195213
• 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; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1; 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; Physiological; Post-Translational Protein Processing; Process; Production; Proteins; Proteolytic Processing; Pyrogens; Role; Signal Transduction; Site; Sterility; Stimulus; Stress; Viral; 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 信号传导对于通过炎症驱动正常组织稳态失调至关重要， 招募和保留造血来源的特殊细胞的过程，这可能而且经常确实 导致受影响器官的生理功能破坏。今天，广泛的发病机制 大多数人类疾病都与急性或慢性炎症有关，这是炎症的关键组成部分。 体内平衡失调，从机制上讲是许多特定的疾病驱动病理的基础。白细胞介素- 1RI 信号传导在受体的两个主要非同源配体 – IL-1α 中的任何一个结合时启动 或IL-1β。在过去的十年中，在了解 IL-1β 的生物学方面取得了真正显着的进展 由于发现 caspase-1 依赖性炎症小体和 caspase-8 作为 IL-1β 的调节剂 生物发生。与 IL-1β 形成鲜明对比，尽管它是第一个被描述的主要人类热原（Dinarello 等 al., 1974)，IL-1α 的生物发生仍然知之甚少。此外，尽管人们越来越欣赏 IL-1α 在许多重要人类疾病发病机制中的贡献、控制因素 IL-1α 的功能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 前体的特定分子修饰，使 IL-1α 在其膜中发挥生理功能 结合形式和分泌形式。在具体目标 1 中，我们将定义特定翻译后的功能作用 对 IL-1α 前体进行修饰，以激发 IL-1α 作为分泌细胞因子和膜结合细胞因子的生物活性 体外。在具体目标 2 中，我们将定义 IL-1α 的分子形式，在体内触发炎症性 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。这些研究应该有助于开发 统一 IL-1α 生物发生的概念模型，使保护性和病理性 IL-1α 驱动宿主成为可能 对病原体、应激和无菌损伤的反应。这些研究有可能改变目前的情况—— 接受了以 IL-1β 为中心的炎症范式，接受了 IL-1α 依赖性促炎启动的概念 损伤或感染部位，是许多人类炎症的引发者和维持者 疾病。