ER stress and neonatal hypoxia ischemia encephalopathy

内质网应激与新生儿缺氧缺血性脑病

• 批准号: 10304130
• 负责人: John H Zhang
• 金额: $ 34.56万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304130
• 关键词: Affect; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Apoptosis; Apoptotic; Attenuated; BCL2 gene; Binding; Blood; Blood flow; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cause of Death; Cell Survival; Cells; Clinical; Complex; Cytochrome P450; Disease; Dissociation; Electron Transport; Emotional; Encephalopathies; Endoplasmic Reticulum; Enzymes; Generations; Genes; Glucose; Goals; Human; Hypoxic-Ischemic Brain Injury; Impairment; In Vitro; Infant; Inflammation; Injections; Injury; Inositol; Interruption; Life; Link; Long-Term Effects; Medical; Membrane; Modeling; Morbidity - disease rate; Morphology; NADP; NADPH-Ferrihemoprotein Reductase; Neurologic; Neurological outcome; Oxygen; PC12 Cells; Pathology; Pathway interactions; Play; Premature Infant; Process; Property; Protein Family; Proteins; Rattus; Reactive Inhibition; Reactive Oxygen Species; Recovery; Role; Signal Pathway; Signal Transduction; Stress; Survivors; Term Birth; Testing; Therapeutic; Transfection; Up-Regulation; attenuation; deprivation; endoplasmic reticulum stress; improved; in vivo; inhibitor; mortality; neonatal brain; neonatal hypoxic-ischemic brain injury; neuroinflammation; neuron apoptosis; neuroprotection; overexpression; protective effect; protein folding; sensor; social; stroke model; therapeutic target; transcription factor; vector

Neonatal hypoxia ischemia (HI) is an injury to the neonatal brain caused by interrupted blood flow. It occurs in 2-4 of 1000 full-term births and 60% of premature infants. It is the leading cause of mortality and morbidity associated with life-long neurological impairments. Endoplasmic reticulum (ER) stress is a major pathology encountered after HI, associated with dysregulation of protein folding leading to apoptosis and inflammation. HI induced ER stress up regulates the pro-apoptotic Inositol requiring enzyme-1 alpha (IRE1α) signaling pathway and is also associated with reactive oxygen species (ROS) accumulation, mainly from the NADPH-dependent cytochrome P450 reductase (NPR) and P450 2E1 (CYP) complex. Bax-inhibitor 1 (BI-1) protein, expressed on ER membrane, has been shown to play a major role in inhibiting ER stress induced signaling pathways. BI-1 can directly bind to IRE1α thus inhibiting this pro-apoptotic pathway as well as reduce ROS accumulation by dissociating the NPR-CYP complex. The objective of this study is to establish BI-1s anti-apoptotic and anti-inflammatory effects in an in vitro oxygen glucose deprivation (OGD) model and in an in vivo neonatal HI rat model as well as to elucidate the mechanisms via which it confers its protective properties. Our central hypothesis is that (1) transfection of cells with Ad- TMBIM6 vector will improve cell viability after OGD as well as help determine BI-s-1s major pathways; (2) overexpression of the BI-1 protein in the brain, via Ad-TMBIM6 injection will improve recovery after neonatal HI by reducing ER stress induced (a) neuronal apoptosis via inhibition of IRE1α signaling pathway and (b) neuroinflammation via dissociation of the NPR-CYP complex and subsequent inhibition of ROS. Specific Aim 1: To determine the role of ER stress signaling pathways in the anti-apoptotic and anti-inflammatory mechanisms of BI-1 in an in vitro Oxygen Glucose Deprivation (OGD) model. Specific Aim 2: To determine whether BI-1 upregulation exerts its anti-apoptotic effects via the IRE1α signaling pathway in an in vivo neonatal HI rat model. Specific Aim 3: To investigate the anti-inflammatory effects of BI-1 overexpression and the signalling pathways involved in an in vivo neonatal HI rat model. The long-term goals of this proposal are to: 1) establish BI-1 as main regulator of ER stress 2) establish BI-1s signaling pathways after neonatal HI; 3) provide a basis for BI-1 as a potential therapeutic target.

新生儿缺血缺血（HI）是由于血流中断引起的新生儿大脑的损伤。它发生在 1000个完整分娩和60％的早产儿中的2-4个。这是死亡率和发病率的主要原因 与终身神经系统障碍有关。 内质网（ER）应力是HI后遇到的主要病理，与失调有关 蛋白质折叠导致凋亡和炎症。 HI诱导的ER应力调节促凋亡 需要酶-1α（IRE1α）信号通路的肌醇，也与活性氧有关 （ROS）积累，主要来自NADPH依赖性细胞色素P450还原酶（NPR）和P450 2E1 （CYP）复合物。 在ER膜上表达的BAX抑制剂1（BI-1）蛋白已显示在抑制ER中起主要作用 应力诱导的信号通路。 BI-1可以直接与IRE1α结合，从而抑制这种促凋亡途径 以及通过分离NPR-CYP复合物来减少ROS的积累。 这项研究的目的是在体外氧中建立BI-1S抗凋亡和抗炎作用 葡萄糖剥夺（OGD）模型和体内新生儿HI大鼠模型以及阐明机制 通过它承认其保护特性。我们的中心假设是（1）用AD-翻译细胞 TMBIM6载体将改善OGD后的细胞活力，并有助于确定BI-S-1S的主要途径。 （2） 通过AD-TMBIM6注射的大脑中BI-1蛋白的过表达将改善新生儿HI后的恢复 通过抑制IRE1α信号通路和（b），通过减少ER应力诱导的（a）神经元凋亡 通过NPR-CYP复合物的解离并随后抑制ROS，神经炎症。具体目标1： 确定ER应力信号通路在抗凋亡和抗炎机制中的作用 在体外氧葡萄糖剥夺（OGD）模型中的BI-1。特定目标2：确定BI-1是否 在体内新生儿HI大鼠模型中，上调通过IRE1α信号通路执行其抗凋亡效应。 特定目的3：研究BI-1过表​​达的抗炎作用和信号通路 参与体内新生儿HI大鼠模型。 该提案的长期目标是：1）将BI-1建立为ER压力的主要调节剂2）建立BI-1S 新生儿HI之后的信号通路； 3）为BI-1作为潜在的治疗靶靶标提供了基础。

项目成果

BMS-470539 Attenuates Oxidative Stress and Neuronal Apoptosis via MC1R/cAMP/PKA/Nurr1 Signaling Pathway in a Neonatal Hypoxic-Ischemic Rat Model.

• DOI: 10.1155/2022/4054938
• 发表时间: 2022
• 期刊: Oxidative medicine and cellular longevity
• 作者: Yu S;Doycheva DM;Gamdzyk M;Gao Y;Guo Y;Travis ZD;Tang J;Chen WX;Zhang JH
• 通讯作者: Zhang JH

Activation of GPR39 with TC-G 1008 attenuates neuroinflammation via SIRT1/PGC-1α/Nrf2 pathway post-neonatal hypoxic-ischemic injury in rats.

• DOI: 10.1186/s12974-021-02289-7
• 发表时间: 2021-10-13
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Xie S;Jiang X;Doycheva DM;Shi H;Jin P;Gao L;Liu R;Xiao J;Hu X;Tang J;Zhang L;Zhang JH
• 通讯作者: Zhang JH

GW0742 activates miR-17-5p and inhibits TXNIP/NLRP3-mediated inflammation after hypoxic-ischaemic injury in rats and in PC12 cells.

• DOI: 10.1111/jcmm.15698
• 发表时间: 2020-11
• 期刊: Journal of cellular and molecular medicine
• 影响因子: 5.3
• 作者: Gamdzyk M;Doycheva DM;Kang R;Tang H;Travis ZD;Tang J;Zhang JH
• 通讯作者: Zhang JH

Activation of MC1R with BMS-470539 attenuates neuroinflammation via cAMP/PKA/Nurr1 pathway after neonatal hypoxic-ischemic brain injury in rats.

• DOI: 10.1186/s12974-021-02078-2
• 发表时间: 2021-01-19
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Yu S;Doycheva DM;Gamdzyk M;Yang Y;Lenahan C;Li G;Li D;Lian L;Tang J;Lu J;Zhang JH
• 通讯作者: Zhang JH

Role of PPAR-β/δ/miR-17/TXNIP pathway in neuronal apoptosis after neonatal hypoxic-ischemic injury in rats.

• DOI: 10.1016/j.neuropharm.2018.08.003
• 发表时间: 2018-09-15
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Gamdzyk M;Doycheva DM;Malaguit J;Enkhjargal B;Tang J;Zhang JH
• 通讯作者: Zhang JH