Harnessing Endogenous Neuroprotection Following ICH

利用 ICH 后的内源性神经保护

• 批准号: 9233211
• 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: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233211
• 关键词: Accounting; Adherens Junction; Affect; Agonist; Animals; Attenuated; Autologous; Blood; Blood - brain barrier anatomy; Blood Preservation; Brain; Brain Edema; Brain Injuries; Cell Proliferation; Cell Survival; Cell surface; Cerebral Edema; Cerebral hemisphere hemorrhage; Cerebrum; Cessation of life; Clinical; Corpus striatum structure; Coupled; Crystallins; Data; Defense Mechanisms; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Enzymes; Event; Functional disorder; G-substrate; GTP-Binding Proteins; Goals; Heat shock proteins; Hormones; Hypothalamic structure; Individual; Injection of therapeutic agent; Intensive Care Units; Learning; Limbic System; Literature; Measures; Mediating; Microcirculation; Molecular; Molecular Chaperones; Movement; Movement Disorders; Mus; Nature; Neocortex; Neuraxis; Neuroglia; Neurologic; Neurologic Deficit; Neurological outcome; Neurons; Neurotransmitters; Parkinson Disease; Pathologic Processes; Patients; Pharmacology; Physiological; Pituitary Gland; Presynaptic Terminals; Production; Protein Kinase C; Proteins; Recovery; Rodent; Rodent Model; Role; Rupture; Schizophrenia; Signal Transduction; Stress-Induced Protein; Stroke; Survivors; System; Testing; Tight Junctions; United States; Whole Blood; base; clinical translation; collagenase; disability; dopaminergic neuron; effective therapy; experimental study; extracellular; improved; improved outcome; innovation; mortality; motivated behavior; mouse model; neuroprotection; neuropsychiatric disorder; neurovascular; neurovascular injury; novel; outcome forecast; patient population; prevent; prospective; public health relevance; receptor; repaired; stroke treatment; treatment strategy

 DESCRIPTION (provided by applicant): At present, there are no consistently effective treatments available for intracerebral hemorrhage (ICH), a common and often fatal stroke subtype. Secondary brain injury after ICH is known to involve disruption of the blood-brain barrier (BBB), followed by formation of brain edema, which is indicative of a poor clinical prognosis. Interestingly, pathological processes, such as ICH, also elicit endogenous defense mechanisms that antagonize the damaging events and mediate repair. We propose to investigate how the brain protects itself from ICH-induced neurovascular injury, and subsequently, augment these protective mechanisms as an innovative and specific treatment strategy. Based on our preliminary observations, we suggest that dopamine-induced stimulation of the dopamine receptor D2 (DRD2) may confer such endogenous protection following ICH. We found increased dopamine levels in the brain of mice subjected to experimental ICH. Furthermore, pharmacological stimulation of the DRD2 attenuated BBB disruption, brain edema, and neurological deficits following ICH. The Gβγ subunit of the DRD2 has been shown to activate extracellular-signal-regulated kinase1/2 (ERK1/2), which in turn activate αB-crystallin (CRYAB), a widely expressed small heat shock protein. CRYAB functions as a molecular chaperone, preventing vital cellular proteins from stress-induced degradation. We believe that CRYAB can protect endothelial barrier-forming tight junction and adherens junction proteins, thus preserving BBB integrity following ICH. We hypothesize that DRD2 stimulation will attenuate BBB disruption, and consequent brain edema formation through Gβγ/ERK-induced activation of CRYAB, thereby improving short- and long-term neurological outcomes after ICH. We will utilize intrastriatal injections of either collagenase (causing spontaneous vessel rupture) or autologous whole blood to induce ICH in rodents. We will measure the concentrations of dopamine and its receptors in the brain of ICH animals. Following that, we will establish the role of DRD2 and its downstream targets in providing neurovascular protection following ICH. Our specific Aim 1 will investigate the role of endogenous and pharmacological DRD2 stimulation in reducing BBB disruption, brain edema formation, and neurological deficits following ICH. Specific Aim 2 will investigate the proposed mechanism of DRD2-induced Gβγ/ERK/CRYAB signaling following ICH. The long-term goals of this proposal are to establish DRD2 agonism as a novel treatment strategy for ICH, demonstrate its underlying protective mechanism, and provide a basis for clinical translation and implementation of DRD2 agonists in patients suffering from ICH.

 描述（由适用提供）：目前，脑部出血（ICH）尚无始终有效的治疗方法，这是一种常见且通常是致命的中风子类型。众所周知，ICH后的继发性脑损伤涉及血脑屏障（BBB）的破坏，然后形成脑水肿，这表明临床预后不良。有趣的是，诸如ICH之类的病理过程也会引起内源性防御机制，使破坏性事件和媒体修复对抗。我们建议研究大脑如何保护自己免受ICH诱导的神经血管损伤的侵害，然后将这些受保护的机制作为一种创新和特定的治疗策略增强。基于我们的初步观察，我们建议多巴胺诱导的对多巴胺受体D2（DRD2）的刺激可能在ICH之后提供这种内源性保护。我们发现经受实验性ICH的小鼠大脑中的多巴胺水平升高。此外，在ICH之后，DRD2的药物刺激减弱了BBB的破坏，脑水肿和神经系统缺陷。 DRD2的Gβγ亚基已被证明可以激活细胞外信号调节的激酶1/2（ERK1/2），这又激活了αB-crystallin（Cryab），这是一种广泛表达的小热激蛋白。 Cryab充当分子伴侣，可防止重要的细胞蛋白导致应力诱导的降解。我们认为，Cryab可以保护形成内皮屏障的紧密连接和粘附连接蛋白，从而在ICH之后保留BBB的完整性。我们假设DRD2模拟会减弱BBB的破坏，因此通过Gβγ/ERK诱导的Cryab激活而形成了脑水肿，从而改善了ICH之后的短期和长期神经学结果。纹状体内注射任何一种胶原酶（导致赞助的血管破裂） 或自体全血以诱导啮齿动物的ICH。我们将测量多巴胺及其受体在ICH动物大脑中的浓度。随后，我们将确定DRD2及其下游靶标在ICH后提供神经血管保护方面的作用。我们的具体目标1将研究内源性和药物DRD2刺激在减少BBB破坏，脑水肿的形成和神经系统防御后的作用。具体目标2将研究ICH后DRD2诱导的Gβ/ERK/CRYAB信号的拟议机制。该提案的长期目标是建立DRD2激动剂作为ICH的新型治疗策略，证明其潜在的保护机制，并为患有ICH患者的患者中DRD2激动剂的临床翻译和实施提供了基础。