Heat Shock Proteins and the Stress Observation System

热激蛋白和应激观察系统

• 批准号: 8645650
• 负责人: Antonio De Maio
• 金额: $ 28.99万
• 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/8645650
• 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.

描述（由申请人提供）：维持稳态是任何生物体的基本条件。细胞保护的最保守的机制是热激蛋白（HSP）的表达，它们参与压力后关键细胞过程的修复和稳定。尽管HSP的主要功能被限制在细胞内事件中，但已发现它们是通过主动过程释放的外部细胞的。我们假设细胞外HSP被导出到“警报”免疫系统，即发生局部应力或损伤。因此，如果局部侮辱应传播，则免疫系统会启用及时的响应。我们创造了这种系统性机制，以感知压力观察系统（SOS）。 SOS的一个重要特征是HSP与质膜衍生的细胞外囊泡（ECV）相关。这些囊泡包含用于靶向特定细胞类型的信息，以传递压力信息。先前的研究表明，HSP70（HSP72）是HSP家族的主要诱导形式，发现嵌入了从应激中恢复的细胞的质膜中。此外，HSP70可以插入人造脂质双层，露天离子电导途径。此外，HSP70从与ECV相关的细胞中释放出来。 HSP70阳性ECV能够与巨噬细胞（M S）相互作用，从而诱导了一种响应，该反应可以改善，预防或捍卫生物体免受随后的侮辱，这与HSP在胁迫耐受性中的作用一致。该应用的目的是阐明Hsp70插入到质膜中的机理以及ECV释放以及与M s的相互作用。这些研究将为蛋白质输出和免疫细胞的激活提供新的细胞机制，这些机制可能构成细胞生物学知识的新支柱以及生物医学研究。此外，我们的研究可能定义了一种新的调节系统，该系统以允许远处细胞之间通信的囊泡形式感知应力的发生。对这种新型沟通系统的理解可能有助于诊断和治疗重症患者。