Regulation of the ER-stress regulator IRE1α - a new approach to the modulation of ischemia-induced mitochondrial dysfunction and cell death

ER 应激调节因子 IRE1α 的调节 - 调节缺血引起的线粒体功能障碍和细胞死亡的新方法

• 批准号: 502515330
• 负责人: Professor Dr. Berend Isermann
• 金额: --
• 依托单位: Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/502515330?language=en
• 关键词: Regulation; ER; stress; regulator; IRE1

Tissue damage due to ischemia reperfusion injury (IRI) remains a major cause of morbidity and mortality. While the tissue injury associated with IRI occurs primarily during reperfusion, different pathways triggered during ischemia prime the injury associated with reperfusion, including increased intracellular calcium flux and mitochondrial-stress associated cell death. Based on recently published data and preliminary work we propose that the endoplasmic reticulum (ER) associated homodimeric protein IRE1α acquires a transient monomeric state during the hypoxic phase, allowing heterodimerization with IP3R1. The IRE1α – IP3R1 heterodimer induces IP3R1 – VDAC1 channel formation at the ER-MAMs (ER-mitochondria associated membranes), which facilitates calcium flux from the ER to mitochondria. This calcium influx primes mitochondrial dysfunction and mitochondrial cell-death promoting effects during reperfusion. Based on further preliminary work we propose that this novel mechanism, which primes ischemic cells for damage, can be inhibited, thus preventing IRI-associated cell- and tissue damage. Among possible candidates regulating the IRE1α – IP3R1 heterodimer induced IP3R1-VDAC1 channel formation is activated protein C (aPC). aPC is a coagulation protease with cytoprotective effects, known to ameliorate IRI through poorly defined intracellular mechanisms. To investigate this novel mechanism and its regulation we wish to address the following aims: Aim-1: Investigate the functional relevance and molecular basis of the IRE1α–IP3R1 interaction; Aim-2: Identify the molecular pathways that regulate the new function of IRE1α at the ER-MAMs during IRI; Aim-3: Investigate the functional relevance and mechanistic interaction of aPC with IRE1α in IRI; We expect that answering these questions will enable us to design targeted approaches to specifically inhibit IRE1α – IP3R1 heterodimerization and thus preventing the mitochondrial calcium overload and mitochondrial dysfunction, which primes cells for damage. We thus expect new insights into mechanisms of ischemia-primed cell- and tissue-damage as well as into mechanisms regulating ER-MAM formation.

缺血再灌注损伤（IRI）引起的组织损伤仍然是发病率和死亡率的主要原因。虽然与IRI相关的组织损伤主要发生在再灌注期间，但在缺血期间触发的不同途径引发与再灌注相关的损伤，包括增加的细胞内钙通量和脑应激相关的细胞死亡。基于最近发表的数据和初步工作，我们提出，内质网（ER）相关的同源二聚体蛋白IRE 1 α获得短暂的单体状态在缺氧阶段，允许异源二聚体与IP 3R 1。IRE 1 α -IP 3R 1异二聚体诱导ER-MAM（ER-线粒体相关膜）处IP 3R 1-VDAC 1通道形成，这促进钙从ER流向线粒体。这种钙内流引发再灌注期间线粒体功能障碍和线粒体细胞死亡促进作用。基于进一步的初步工作，我们提出，这种新的机制，它引发缺血细胞的损伤，可以被抑制，从而防止虹膜相关的细胞和组织损伤。在调节IRE 1 α -IP 3R 1异二聚体诱导的IP 3R 1-VDAC 1通道形成的可能候选物中，有活化蛋白C（aPC）。aPC是一种具有细胞保护作用的凝血蛋白酶，已知通过不明确的细胞内机制改善IRI。为了研究这种新的机制及其调控，我们希望解决以下目标：目的-1：研究IRE 1 α-IP 3R 1相互作用的功能相关性和分子基础;目的-2：鉴定在IRI期间调节IRE 1 α在ER-MAMs的新功能的分子途径;目的-3：研究IRI中aPC与IRE 1 α的功能相关性和机制相互作用;目的-3：研究IRE 1 α与IRE 1 α的相互作用。我们希望回答这些问题将使我们能够设计有针对性的方法来特异性抑制IRE 1 α -IP 3R 1异源二聚化，从而防止线粒体钙超载和线粒体功能障碍，从而引发细胞损伤。因此，我们期待新的见解缺血引发的细胞和组织损伤的机制，以及调节ER-MAM形成的机制。