Heat shock proteins and neuroprotection in cerebral ischemia

热休克蛋白与脑缺血的神经保护

• 批准号: 10001425
• 负责人: Jun Chen
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001425
• 关键词: Actins; Adult; Apoptotic; Blood - brain barrier anatomy; Blood Preservation; Brain; Brain Injuries; Cells; Cellular Structures; Central Nervous System Diseases; Cerebral Ischemia; Cerebrum; Clinical; Cytoskeletal Modeling; Cytoskeleton; Data; Development; Disabled Persons; Disease; Edema; Endothelial Cells; Endothelium; Event; Exhibits; Extravasation; Future; Gelatinase A; Gene Targeting; Genes; Glucose; HSPB1 gene; Heat shock proteins; Hemorrhage; Immune; Impairment; In Vitro; Infarction; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Ischemia; Ischemic Stroke; Lentivirus Vector; Liquid substance; MMP2 gene; Mediating; Medical; Middle Cerebral Artery Occlusion; Military Personnel; Modeling; Molecular Chaperones; Mus; NF-kappa B; Nervous System Physiology; Neurologic; Neurological outcome; Oxygen; Pathogenesis; Pathologic; Patients; Permeability; Plasma Proteins; Production; Protective Agents; Protein Family; Proteins; Quality of life; Reperfusion Injury; Reperfusion Therapy; Rodent; Role; Signaling Molecule; Stroke; Structure; Testing; Therapeutic; Therapeutic Agents; Thrombolytic Therapy; Time; Transfection; Transgenic Mice; Transgenic Organisms; Tumor-infiltrating immune cells; United States; Veterans; actin depolymerizing factor; aged; base; blood-brain barrier disruption; blood-brain barrier function; blood-brain barrier permeabilization; brain endothelial cell; brain parenchyma; cell type; deprivation; disability; improved; improved outcome; in vivo; innovation; intravenous administration; intravenous injection; knock-down; member; nervous system disorder; neuroprotection; novel; novel therapeutic intervention; overexpression; polymerization; post stroke; prevent; protective effect; public health relevance; stroke survivor; stroke therapy; stroke victims; white matter injury; young adult

DESCRIPTION (provided by applicant): Abstract Stroke is a major medical concern for United States military veterans. Disruption of the blood-brain barrier (BBB) is a catastrophic event in the pathogenesis of ischemic/reperfusion (I/R) brain injury. Our recent studies suggested that structural alterations in brain endothelial cells (EC), including abnormal actin polymerization and the resulting redistribution of junctional proteins, is a novel mechanism responsible for early BBB leakage after I/R (30 min-3h); while matrix metalloproteinase (MMP) 2/9 activation, a predominant mechanism thought to contribute to post-stroke BBB disruption, contribute to the BBB leakage to larger molecules (>40kDa) in a relatively delayed manner. Therefore, restoring EC structure/function may offer an innovative therapeutic strategy for early BBB protection against I/R, while blocking MMP2/9 may provide a relatively delayed protection to BBB. Heat shock protein 27 (HSP27), a member of the small heat shock protein family, confers neuroprotection in several models of CNS diseases, including I/R brain injury. In addition to its well-known protein chaperone and anti-apoptotic functions, HSP27 may act as a potent actin depolymerization factor in certain cell types such as EC, thus potentially inhibiting actin polymerization-mediated BBB disruption. Further, HSP27 may inhibit the activation of NF-kappaB, a central signaling molecule for the production of MMP2/9 and pro-inflammatory mediators. We recently observed that HSP27 is transiently upregulated in brain EC after I/R. However, the precise role of HSP27 in the functional integrity of EC following I/R and the underlying mechanism remain unknown. Using transgenic mice overexpressing HSP27 and the lentiviral gene-transfection approach, we have obtained novel pilot data showing that HSP27 overexpression protects the endothelium from I/R-induced hyperpermeability in vitro and in vivo; that HSP27 inhibited oxygen glucose deprivation-induced actin polymerization and redistribution of junctional proteins in EC; and that intravenous administration of HSP27 containing a cell permeable transduction domain (TAT-HSP27) enabled rapid delivery of the protein into brain micro-vasculatures, reduced BBB damage and inhibited MMP2/9 activity after I/R. This proposal will further explore the BBB protective effect of HSP27 on I/R brain injury and elucidate the underlying mechanisms. The central hypothesis to be tested is that HSP27 protects BBB against I/R injury by stabilizing EC cytoskeletal organization in microvasculature early after I/R and inhibiting the production of MMP2/9 as well as pro-inflammatory proteins. The following specific aims are proposed: Aim 1: To determine whether endothelial targeted overexpression of HSP27 is sufficient to provide early protection on BBB integrity and to confer long term protection against cerebral I/R. Aim 2: Test the hypothesis that HSP27 protects endothelial integrity following I/R by dualistic mechanisms: stabilizing the actin cytoskeleton and inhibiting NFkB-dependent MMP2/9 production and inflammation. Aim 3: Test the hypothesis that post-stroke delivery of TAT-HSP27 to EC protects against BBB damage and improves outcomes in both young adult and aged mice. The proposed study attempts to develop HSP27 into a novel, clinically feasible therapeutic strategy to ameliorate post-stroke BBB damage, brake down the progression of brain damage, and improve long-term neurological functions in stroke victims. The successful completion of this proposed study will help improve the quality of life for veterans suffering from stroke.

描述（由申请人提供）：

项目成果

Neuroprotection against ischemic stroke requires a specific class of early responder T cells in mice.

• DOI: 10.1172/jci157678
• 发表时间: 2022-08-01
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Cai, Wei;Shi, Ligen;Zhao, Jingyan;Xu, Fei;Dufort, Connor;Ye, Qing;Yang, Tuo;Dai, Xuejiao;Lyu, Junxuan;Jin, Chenghao;Pu, Hongjian;Yu, Fang;Hassan, Sulaiman;Sun, Zeyu;Zhang, Wenting;Hitchens, T. Kevin;Shi, Yejie;Thomson, Angus W.;Leak, Rehana K.;Hu, Xiaoming;Chen, Jun
• 通讯作者: Chen, Jun

Promises and limitations of immune cell-based therapies in neurological disorders.

• DOI: 10.1038/s41582-018-0028-5
• 发表时间: 2018-09
• 期刊: Nature reviews. Neurology
• 作者: Hu X;Leak RK;Thomson AW;Yu F;Xia Y;Wechsler LR;Chen J
• 通讯作者: Chen J

Rapid endothelial cytoskeletal reorganization enables early blood-brain barrier disruption and long-term ischaemic reperfusion brain injury.

• DOI: 10.1038/ncomms10523
• 发表时间: 2016-01-27
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Shi Y;Zhang L;Pu H;Mao L;Hu X;Jiang X;Xu N;Stetler RA;Zhang F;Liu X;Leak RK;Keep RF;Ji X;Chen J
• 通讯作者: Chen J

Peroxisome proliferator-activated receptor γ (PPARγ): A master gatekeeper in CNS injury and repair.

过氧化物酶体增殖物激活受体γ (PPARγ)：中枢神经系统损伤和修复的主要看门人

• DOI: 10.1016/j.pneurobio.2017.10.002
• 发表时间: 2018-04
• 期刊: Progress in neurobiology
• 影响因子: 6.7
• 作者: Cai W;Yang T;Liu H;Han L;Zhang K;Hu X;Zhang X;Yin KJ;Gao Y;Bennett MVL;Leak RK;Chen J
• 通讯作者: Chen J

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke.

• DOI: 10.1161/circresaha.116.308427
• 发表时间: 2017-02-03
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Hu X;De Silva TM;Chen J;Faraci FM
• 通讯作者: Faraci FM