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.

新生儿缺氧缺血（HI）是由血流中断引起的新生儿脑损伤。它发生在

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

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

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