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.

项目概要/摘要 中风是成人神经功能障碍的主要原因，幸存者常常因以下原因留下永久性缺陷： 缺血引起的脑损伤导致的神经元损失。目前还没有成功的治疗方法 一旦发生脑损伤，中风患者即可恢复正常功能，但康复除外 疗法，其促进完全康复的能力有限。在临床前研究中，刺激治疗 用来自未受伤的神经组织的新的神经解剖学连接替换受损的通路， 被称为神经可塑性的过程已被证明是改善功能恢复的有前途的策略 受伤后。我们的实验室使用了抗体疗法来阻断神经突抑制蛋白Nogo- A 促进神经可塑性并显着改善受影响动物的功能结果 实验性中风。然而，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。我们之前已经证明 Nogo-A 可以改变神经 生长因子 (NGF) 依赖性神经营养素信号传导对神经元存活和神经突产生负面影响 生长出来的。该提案的目的是验证 TrkA 信号传导的破坏是中风的结果 诱导 Nogo-A 表达，并验证旨在重建可塑性促进的方法 NGF 受体（TrkA 和 p75NTR）的神经营养素信号传导。我们的中心假设是治疗 规避或阻断 Nogo-A 对 TrkA 的抑制，以刺激 TrkA 介导的神经营养蛋白信号通路 将增强神经可塑性并改善缺血性中风后的恢复。在目标 1 中，我们将使用primary 培养神经元以检查受 Nogo-A 影响的 TrkA 和 p75NTR 神经营养蛋白信号传导机制 旨在规避或阻断 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 对体内缺血性中风后 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 Nogo-A 敲除小鼠。将使用生化和免疫组织化学技术 评估中风对 NGF 受体、其下游效应器的影响以及这些受体之间的关联 野生型和基因敲除小鼠中 Nogo-A 受体。在目标 3 中，我们将评估治疗干预措施： 规避或阻断 Nogo-A 对 TrkA 受体的抑制作用，以促进中风后的恢复。我们 将使用我们经过充分研究的体内中风模型来确定抗Nogo-A治疗的程度 抗体或新型选择性 TrkA 激动剂藤黄酰胺会影响 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的神经营养蛋白介导的理解 信号机制因中风损伤而改变。因此，拟议的工作将为 中风康复的新颖且有前途的疗法，这对于设计和治疗至关重要 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