Heat Shock Proteins and the Stress Observation System

热激蛋白和应激观察系统

• 批准号: 8295387
• 负责人: Antonio De Maio
• 金额: $ 27.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8295387
• 关键词: Affinity; Artificial Membranes; Biological Markers; Biological Preservation; Biomedical Research; Blood Circulation; Cell membrane; Cell physiology; Cells; Cellular Membrane; Cellular biology; Code; Coin; Communication; Consensus; Critical Illness; Development; Diagnosis; Distant; Endocytosis; Endotoxemia; Environment; Event; Heat shock proteins; Heat-Shock Proteins 70; Homeostasis; Immune; Immune system; Injury; Investigation; Ions; Knowledge; Life; Lipid Bilayers; Membrane; Membrane Biology; Membrane Proteins; Modeling; Molecular Chaperones; Multivesicular Body; Organism; Pathway interactions; Patients; Phosphatidylserines; Process; Protein Export Pathway; Protein Family; Proteins; Proteomics; Reporting; Role; Sepsis; Signal Transduction; Signaling Molecule; Solutions; Specificity; Stress; Surface; System; TNF gene; Testing; Transmembrane Domain; Vesicle; base; biological adaptation to stress; cell injury; cell type; extracellular; in vivo; macrophage; novel; polypeptide; prevent; protein activation; receptor; repaired; response; seal; stress tolerance

DESCRIPTION (provided by applicant): Preservation of homeostasis is a fundamental condition for any organism. The most conservative mechanism for cellular protection is the expression of heat shock proteins (hsp), which are involved in the repair and stabilization of key cellular processes after stress. Although the primary function of hsp is circumscribed to intracellular events, they have been found outside cells, released by an active process. We hypothesize that extracellular hsp are exported to "alert" the immune system that a localized stress or injury has occurred. Therefore, the immune system is primed to mount a timely response in case the localized insult should propagate. We have coined this systemic mechanism to sense stress the stress observation system (SOS). An important feature of the SOS is that hsp are released associated with extracellular vesicles (ECV) derived from the plasma membrane. These vesicles contain information for targeting specific cell types for the delivery of the stress information. Prior investigations have shown that Hsp70 (Hsp72), the major inducible form of the hsp family, was found embedded in the plasma membrane of cells recovering from a stress. In addition, Hsp70 can be inserted into artificial lipid bilayers, openin ion conductance pathways. Moreover, Hsp70 was released from cells associated with ECV. Hsp70-positive ECV is able to interact with macrophages (M s), inducing a response that primes cells to ameliorate, prevent, or defend the organism from subsequent insults, which is consistent with the role of hsp in stress tolerance. The objective of this application is to elucidate the mechanisms of Hsp70 insertion into the plasma membrane and ECV release and interaction with M s. These investigations will provide novel cellular mechanisms for protein export and activation of immune cells, which are likely to constitute new pillars of knowledge for cellular biology as well as biomedical research. Moreover, our studies may define a new regulatory system that senses the occurrence of stress in the form of vesicles that permit the communication between distant cells. An understanding of this novel communication system may be of help in the diagnosis and treatment of critically ill patients. PUBLIC HEALTH RELEVANCE: Extracellular hsp are part of the stress response, but at a systemic level. Hsp70 is released into circulation to alert the organism that stress has occurred, and the presence of Hsp70 in circulation may prime cells of the innate immune system after the occurrence of a localized injury to prepare for the potential propagation of the insult and offer protection from subsequent stresses.

描述（由申请人提供）：保持体内平衡是任何生物体的基本条件。最保守的细胞保护机制是热休克蛋白（hsp）的表达，它参与应激后关键细胞过程的修复和稳定。尽管 hsp 的主要功能仅限于细胞内事件，但它们也被发现存在于细胞外，由活跃过程释放。我们假设细胞外热休克蛋白被输出以“警告”免疫系统局部应激或损伤已经发生。因此，免疫系统准备好及时做出反应，以防局部损伤扩散。我们创造了这种系统机制来感知压力——压力观察系统（SOS）。 SOS 的一个重要特征是 hsp 的释放与质膜衍生的细胞外囊泡 (ECV) 相关。这些囊泡包含针对特定细胞类型的信息，以传递应激信息。先前的研究表明，Hsp70（Hsp72）是 hsp 家族的主要诱导形式，被发现嵌入从应激中恢复的细胞的质膜中。此外，Hsp70 可以插入人工脂质双层，打开离子电导通路。此外，Hsp70从与ECV相关的细胞中释放。 Hsp70 阳性 ECV 能够与巨噬细胞 (M s) 相互作用，诱导细胞做出反应，以改善、预防或保护生物体免受后续损伤，这与 hsp 在应激耐受中的作用一致。本申请的目的是阐明 Hsp70 插入质膜和 ECV 释放以及与 M s 相互作用的机制。这些研究将为蛋白质输出和免疫细胞激活提供新的细胞机制，这可能构成细胞生物学和生物医学研究的新知识支柱。此外，我们的研究可能会定义一种新的调节系统，该系统以允许远处细胞之间通讯的囊泡形式感知压力的发生。了解这种新颖的通信系统可能有助于危重患者的诊断和治疗。 公共卫生相关性：细胞外热休克蛋白是应激反应的一部分，但处于全身水平。 Hsp70 被释放到循环中，以警告生物体已经发生应激，并且循环中 Hsp70 的存在可以在发生局部损伤后启动先天免疫系统的细胞，为潜在的损伤传播做好准备，并提供保护免受后续损伤的影响。压力。