Novel Insights into Ischemic-Induced Cardiac Remodeling

对缺血引起的心脏重塑的新见解

基本信息

批准号：
9934694
负责人：
John Winter Calvert
金额：
$ 1.82万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-15 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9934694
关键词：
Acute Advanced Glycosylation End Products Amino Acids Antioxidants Apoptotic Attenuated Biochemical Biology Brain Cardiac Caring Cell Culture System Cell physiology Cells Cleaved cell Complement Factor B Cytoprotection Data Development Enzyme Precursors Enzymes Excision Fibrosis Heart Heart failure Hour Hypertrophy Inflammation Injury Knowledge Length Link Literature MAP3K5 gene Maintenance Mediating Mus Myocardial Ischemia Myocardial dysfunction N(6)-carboxymethyllysine Nature Neurons Oxidative Stress Oxidoreductase Parkinson Disease Pathologic Peptide Hydrolases Peptides Physiological Play Proteins Recombinant adeno-associated virus (rAAV)Regulation Reperfusion Injury Reperfusion Therapy Reporting Research Role Signal Transduction Stimulus Stress TXN gene Tertiary Protein Structure Testing Transcriptional Regulation Transforming Growth Factors Treatment Efficacy Up-Regulation Wild Type Mouse arginyllysine base biological adaptation to stress cardiogenesis cardioprotection design dimer glycation in vivo in vivo Model insight novel repaired response ubiquitin-protein ligase

项目摘要

Project Summary DJ-1 is a cytoprotective protein that is activated by oxidative stress. Due in large part to the association of DJ-1 with Parkinson's Disease, most studies aimed at investigating its role in response to pathological stimuli have been confined to the brain or neuronal cells. However, DJ-1 is expressed in the heart where it also possesses cytoprotective actions. Studies indicate that DJ-1 plays an important role in multiple cellular processes, including oxidative stress response, anti-apoptotic signaling, and transcriptional regulation. However, the cellular mechanisms underlying these reported actions remain largely unknown. Given that DJ-1 is a small, dimeric, single-domain protein, it either possesses multiple functions to account for these actions or there is a single biochemical activity that explains all of them. What is known is that DJ-1 is activated by the removal of a 15-amino acid peptide at its C terminus in response to oxidative stress. We recently provided the first evidence that DJ-1 is activated within hours following the onset of acute myocardial ischemia-reperfusion (I/R). Preliminary studies from our lab demonstrate that cardiac DJ-1 remains active for up to 7 days following the onset of ischemic injury. Furthermore, our studies revealed that DJ-1 deficient mice displayed worse cardiac dysfunction in response to ischemic-induced heart failure compared to wild-type mice. Elevated levels of hypertrophy, fibrosis, and inflammation accompanied the worse cardiac dysfunction in the DJ-1 deficient mice. More importantly, we provide novel evidence that the delivery of the active form of DJ-1 using recombinant adeno-associated virus 9 (AAV9-DJ1WTΔC) reduces the development of ischemic-induced heart failure. This is the first and only demonstration that an active form of DJ-1 provides cytoprotection in an in vivo model of injury. In this proposal, we will expand on our previous findings and attempt to fill knowledge gaps in the literature regarding the cellular actions of DJ-1. 3 specific aims have been proposed. Aim 1 will determine if DJ- 1 is a novel cardiac deglycase that opposes glycative stress. Aim 2 will determine if DJ-1 attenuates ischemic- induced heart failure by promoting the cardioprotective actions of thioredoxin. Aim 3 will determine if DJ-1 opposes TGF-β signaling by regulating the cardiac expression of Arkadia.

项目概要 DJ-1 是一种由氧化应激激活的细胞保护蛋白，很大程度上是由于 DJ-1 的结合。对于帕金森病，大多数旨在调查其对病理刺激反应的作用的研究都已 DJ-1 只在大脑或神经细胞中表达，但它也在心脏中表达。研究表明 DJ-1 在多种细胞过程中发挥重要作用，包括氧化应激反应、抗凋亡信号传导和转录调控。鉴于 DJ-1 是一种小分子，因此这些报道的作用背后的细胞机制仍然未知。二聚体、单结构域蛋白质，它要么具有多种功能来解释这些作用，要么存在单一的生化活性可以解释所有这些现象，众所周知，DJ-1 是通过去除 a 来激活的。 C 末端的 15 个氨基酸肽对氧化应激的反应我们最近提供了第一个证据。 DJ-1 在急性心肌缺血再灌注 (I/R) 发生后数小时内被激活。我们实验室的初步研究表明，心脏 DJ-1 在术后 7 天内仍保持活跃状态。此外，我们的研究表明，DJ-1 缺陷小鼠的心脏功能较差。与野生型小鼠相比，缺血性心力衰竭导致的功能障碍。 DJ-1 缺陷小鼠的心脏肥大、纤维化和炎症伴随着更严重的心脏功能障碍。更重要的是，我们提供了新的证据，证明使用重组载体递送活性形式的 DJ-1 腺相关病毒 9 (AAV9-DJ1WTΔC) 可减少缺血性心力衰竭的发生。是第一个也是唯一的证明 DJ-1 的活性形式在体内模型中提供细胞保护作用在本提案中，我们将扩展我们之前的发现并尝试填补相关领域的知识空白。关于 DJ-1 细胞作用的文献提出了 3 个具体目标，目标 1 将确定 DJ-1 是否有效。 1 是一种对抗糖化应激的新型心脏去糖酶，目标 2 将确定 DJ-1 是否可以减轻缺血。通过促进硫氧还蛋白的心脏保护作用诱导心力衰竭目标 3 将确定 DJ-1 是否有效。通过调节 Arkadia 的心脏表达来对抗 TGF-β 信号传导。