Novel approaches to stimulating neurotrophin signaling for stroke recovery

刺激神经营养蛋白信号传导以促进中风恢复的新方法

• 批准号: 10530668
• 负责人: GWENDOLYN LOUISE KARTJE
• 金额: $ 30.19万
• 依托单位: CHICAGO ASSN FOR RESEARCH & EDUC IN SCI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10530668
• 关键词: Adult; Affect; Agonist; Amides; Animals; Antibodies; Antibody Therapy; Axon; Biochemical; Brain Injuries; Ceramides; Clinical Trials; Data; Effectiveness; Emotional; Family; Female; Foundations; Future; General Population; Goals; Immunotherapy; In Vitro; Injury; Ischemia; Ischemic Stroke; Knock-out; Knockout Mice; Knowledge; Laboratories; Left; Mediating; Molecular; Mus; NGFR Protein; Nerve Block; Nerve Growth Factor Receptors; Nerve Growth Factors; Neurites; Neuroanatomy; Neurodegenerative Disorders; Neurologic; Neuronal Plasticity; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 1; Nogo protein; Outcome; Pathway interactions; Patients; Phosphorylation; Process; Publishing; Rattus; Recovery; Recovery of Function; Rehabilitation therapy; Research; Role; Signal Pathway; Signal Transduction; Site; Stroke; Survivors; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; United States; Up-Regulation; Wild Type Mouse; Work; behavioral outcome; design; disability; functional improvement; functional outcomes; improved; in vivo; innovation; ischemic injury; male; neural; neuron loss; neuronal survival; neurotransmission; neurotrophic factor; novel; novel strategies; overexpression; post stroke; preclinical study; receptor; stroke model; stroke patient; stroke recovery; stroke rehabilitation; stroke therapy

Project Summary/Abstract Stroke is a leading cause of adult neurologic disability with survivors often left with permanent deficits due to neuronal loss resulting from ischemia-induced brain injury. There are currently no successful treatments to restore normal function to stroke patients once brain damage has occurred, with the exception of rehabilitation therapy, which is limited in its ability to promote full recovery. In preclinical studies, treatments that stimulate the replacement of damaged pathways with new neuroanatomical connections from uninjured neural tissue, a process known as neuroplasticity, have proven to be promising strategies for improving recovery of function after injury. Our laboratory has used antibody therapy directed at blocking the neurite inhibitory protein Nogo- A to promote neuroplasticity and significantly improve the functional outcome of animals affected by experimental stroke. However, the cellular and molecular mechanisms responsible for anti-Nogo-A antibody- mediated recovery remain largely unknown. We have previously demonstrated that Nogo-A alters nerve growth factor (NGF)-dependent neurotrophin signaling to negatively influence neuronal survival and neurite outgrowth. The goal of this proposal is to verify that disruption of TrkA signaling is a consequence of stroke- induced Nogo-A expression, and to validate approaches designed to re-establish plasticity-promoting neurotrophin signaling by NGF receptors (TrkA and p75NTR). Our central hypothesis is that treatments that circumvent or block Nogo-A inhibition of TrkA to stimulate TrkA-mediated neurotrophin signaling pathways will enhance neuroplasticity and improve recovery following ischemic stroke. In Aim 1 we will use primary neurons in culture to examine TrkA and p75NTR neurotrophin signaling mechanisms affected by Nogo-A and test strategies designed to circumvent or block the inhibitory effect of Nogo-A on TrkA signaling. In Aim 2 we will determine the role of Nogo-A on TrkA-mediated neurotrophin signaling following ischemic stroke in vivo using neuron-specific Nogo-A knockout mice. Biochemical and immunohistochemical techniques will be used to assess the effect of stroke on NGF receptors, their downstream effectors and the association of these receptors with Nogo-A in wild type and knockout mice. In Aim 3 we will evaluate therapeutic interventions that circumvent or block the inhibitory action of Nogo-A on the TrkA receptor to enhance recovery after stroke. We will use our well-studied in vivo stroke model to determine the extent to which treatment with anti-Nogo-A antibody or the novel selective TrkA agonist gambogic amide affects NGF signaling and stroke recovery. Together, the results from this proposal will increase our understanding of underlying neurotrophin-mediated signaling mechanisms altered as a result of stroke injury. Thus, the proposed work will provide a foundation for novel and promising therapies for stroke rehabilitation, which is critically important for the design and successful outcome of future clinical trials.

项目摘要/摘要 中风是成人神经疾病的主要原因，幸存者通常由于 缺血引起的脑损伤导致的神经元丧失。目前没有成功的治疗方法 一旦发生脑损伤，恢复中风患者的正常功能，除了康复外 治疗，其促进完全康复的能力有限。在临床前研究中，刺激的治疗 用未受伤的神经组织的新神经解剖连接代替受损途径 被称为神经可塑性的过程已被证明是改善功能恢复的有希望的策略 受伤后。我们的实验室使用了旨在阻断神经突抑制性蛋白质的抗体治疗 a促进神经塑性并显着改善受动物影响的功能结果 实验性中风。但是，负责抗Nogo-A抗体的细胞和分子机制 介导的恢复在很大程度上仍然未知。我们以前已经证明了Nogo-A可以改变神经 生长因子（NGF）依赖性神经营养蛋白信号传导，对神经元的生存和神经突。 出生。该提案的目的是验证TRKA信号的破坏是中风的结果 诱导NoGo-A表达，并验证旨在重新建立可塑性的方法 NGF受体（TRKA和P75NTR）神经营养蛋白信号传导。我们的核心假设是治疗 绕过TRKA的NOGO-A抑制作用，以刺激TRKA介导的神经营养蛋白信号通路 缺血性中风后会增强神经可塑性并改善恢复。在AIM 1中，我们将使用主要 培养中的神经元检查受Nogo-A和 旨在规避或阻止NoGo-A对TRKA信号传导的抑制作用的测试策略。在目标2中我们 将确定Nogo-A在体内缺血性中风后TRKA介导的神经营养蛋白信号传导的作用 使用神经元特异性的Nogo-A基因敲除小鼠。将使用生化和免疫组织化学技术 为了评估中风对NGF受体的影响，其下游效应子及其关联 野生型和基因敲除小鼠的受体。在AIM 3中，我们将评估治疗干预措施 绕过或阻断Nogo-A对TRKA受体的抑制作用，以增强中风后的恢复。我们 将使用我们研究良好的体内中风模型来确定抗Nogo-A处理的程度 抗体或新型的选择性TRKA激动剂Gambogic酰胺会影响NGF信号传导和中风恢复。 总之，该提案的结果将增加我们对潜在神经营养蛋白介导的理解 信号传导机制因中风损伤而改变。因此，拟议的工作将为 中风康复的新颖和有前途的疗法，这对于设计至关重要 未来临床试验的成功结果。

项目成果

Improved Functional Outcome After Peripheral Nerve Stimulation of the Impaired Forelimb Post-stroke.

• DOI: 10.3389/fneur.2021.610434
• 发表时间: 2021
• 期刊: Frontiers in neurology
• 影响因子: 3.4
• 作者: Tsai SY;Schreiber JA;Adamczyk NS;Wu JY;Ton ST;Hofler RC;Walter JS;O'Brien TE;Kartje GL;Nockels RP
• 通讯作者: Nockels RP

A Potent Inhibitor of Aminopeptidase P2 Reduces Reperfusion Injury in Models of Myocardial Infarction and Stroke.

氨基肽酶 P2 的有效抑制剂可减少心肌梗死和中风模型的再灌注损伤。

• DOI: 10.1124/jpet.121.000875
• 发表时间: 2022
• 期刊: The Journal of pharmacology and experimental therapeutics
• 作者: Lenz,MorganR;Tsai,Shih-Yen;Roessler,AnneE;Wang,Yang;Sethupathi,Periannan;Jones,WKeith;Kartje,GwendolynL;Simmons,WilliamH
• 通讯作者: Simmons,WilliamH