Harnessing Endogenous Neuroprotection Following ICH

利用 ICH 后的内源性神经保护

• 批准号: 9113729
• 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/9113729
• 关键词: Accounting; Adherens Junction; Affect; Agonist; Animals; Attenuated; Autologous; Biological Preservation; Blood; Blood - brain barrier anatomy; 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; DRD2 gene; Data; Defense Mechanisms; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Enzymes; Event; Functional disorder; 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; Neurological outcome; Neurons; Neurotransmitters; Parkinson Disease; Pathologic Processes; Patients; 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; Translations; United States; Whole Blood; base; collagenase; disability; dopaminergic neuron; effective therapy; 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; research study; 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（由申请人提供）：目前，脑出血（ICH）一直没有有效的治疗方法，脑出血是一种常见且通常致命的中风亚型，已知 ICH 后继发性脑损伤涉及血脑屏障（BBB）的破坏。 ），随后形成脑水肿，这表明临床预后不良，例如 ICH 等病理过程也会引发对抗损害事件并介导的内源性防御机制。我们提出大脑如何保护自身免受脑出血引起的神经血管损伤，并随后将这些保护机制作为一种创新和特异性的治疗策略来增强，根据我们的初步研究观察，我们建议多巴胺诱导的多巴胺受体刺激。 D2 (DRD2) 可能在 ICH 后赋予这种内源性保护作用。我们发现，实验性 ICH 小鼠的大脑中多巴胺水平升高。此外，DRD2 的药物刺激可减轻 BBB 破坏、脑水肿和神经系统损伤。 DRD2 的 Gβγ 亚基已被证明可以激活细胞外信号调节激酶 1/2 (ERK1/2)，进而激活 αB-晶状体蛋白 (CRYAB)，这是一种广泛表达的小热休克蛋白。作为分子伴侣，防止重要细胞蛋白因应激引起的降解。我们相信 CRYAB 可以保护内皮屏障形成紧密连接和粘附连接蛋白，从而保持 BBB 完整性。我们认为，DRD2 刺激将通过 Gβγ/ERK 诱导的 CRYAB 激活来减轻 BBB 破坏以及随后的脑水肿形成，从而改善 ICH 后的短期和长期神经学结果。血管自发破裂） 我们将测量 ICH 动物大脑中多巴胺及其受体的浓度，然后确定 DRD2 及其下游靶点在 ICH 后提供神经血管保护中的作用。目标 1 将研究内源性和药理学 DRD2 刺激在减少 ICH 后 BBB 破坏、脑水肿形成和神经功能缺损方面的作用。具体目标 2 将研究 DRD2 诱导的拟议机制。 ICH后的Gβγ/ERK/CRYAB信号传导该提案的长期目标是将DRD2激动剂建立为ICH的新型治疗策略，证明其潜在的保护机制，并为DRD2激动剂在患者中的临床转化和实施提供基础。患有脑出血。