Translational potential of the internalization of Nogo-A receptor to enhance axonal regeneration after stroke

Nogo-A 受体内化增强中风后轴突再生的转化潜力

基本信息

批准号：
10062753
负责人：
RAYUDU GOPALAKRISHNA
金额：
$ 45.38万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062753
关键词：
Adult Affinity Antibodies Antioxidants Binding Brain Brain-Derived Neurotrophic Factor Catechin Cause of Death Cell surface Cessation of life Chemosensitization Chondroitin Sulfate Proteoglycan Chronic Clinical Complement Consumption Cues Cyclic AMP Dose Epigallocatechin Gallate Generations Green tea Growth Inhibitors Human Laminin Receptor Lead Mediating Middle Cerebral Artery Occlusion Myelin Associated Glycoprotein NGFR Protein Natural Products Nerve Regeneration Neurites Neurologic Neuronal Injury Neuronal Plasticity Neurons Outcome Pathway interactions Peptides Pharmaceutical Preparations Pharmacology Physiological Processes Predisposition Prevention Protein Kinase Proteins Reactive Oxygen Species Recovery Recovery of Function Reperfusion Therapy Reporting Second Messenger Systems Signal Transduction Stroke Surface axon growth axon regeneration base behavioral study chronic stroke desensitization disability drinking water improved ischemic injury mouse model nanomolar neurite growth neurotrophic factor novel oligodendrocyte-myelin glycoprotein polyphenol post stroke pre-clinical receptor rehabilitation strategy response stroke recovery stroke therapy treatment optimization

项目摘要

Project Summary/Abstract Stroke is a major cause of disability and a leading cause of death. Chronic stroke therapy requires a functional recovery by overcoming axonal growth inhibitors such as Nogo-A. Although drugs are being developed, currently, there are no clinically proven drugs for recovery from stroke and other neuronal injuries. Evaluating the efficacy of natural products that are safe, neuroprotective, neuroregenerative, and inexpensive would complement ongoing efforts. Following ischemic injury, axonal growth is enhanced by the conventional approach of “extrinsically” blocking axonal growth inhibitors. Our hypothesis is that axonal growth can also be achieved by “intrinsically” decreasing the susceptibility of neurons to axonal growth inhibitors. Combining this intrinsic approach with neurotrophic activity could be even more effective. At low nanomolar concentrations, green tea polyphenols, such as epigallocatechin-3-gallate (EGCG), elevate the cAMP-Epac (exchange protein directly activated by cAMP) pathway and induce internalization of Nogo-A receptor (NgR1) and other related receptors. EGCG thereby blocks the actions of not only Nogo-A, but also diverse axonal growth inhibitors. In parallel, EGCG also activates the reactive oxygen species (ROS)-protein kinase Ce pathway and potentiates the actions of neurotrophins, such as brain-derived neurotrophic factor (BDNF). The combined effects of EGCG (desensitization of neurons to axonal growth inhibitors and potentiation of neurotrophins) lead to long axonal growth and functional recovery, which may be exploited for chronic stroke therapy. In the first aim, we will use primary cortical neurons to determine whether the EGCG-induced cAMP- Epac pathway can cause internalization and degradation of NgR1 and its coreceptors as well as other related receptors. We will ascertain whether this correlates with the EGCG-induced decrease in the action of Nogo-A and other axonal growth inhibitors. We will also determine if EGCG-induced parallel activation of the ROS- PKCe pathway can potentiate the actions of neurotrophins, such as BDNF, and enhance long neurite growth. In the second aim, we will use the mouse model of MCAO (middle cerebral artery occlusion/reperfusion) to induce stroke. For chronic stroke therapy, we will administer a safe dose of EGCG daily through drinking water. We will determine whether EGCG decreases the neuronal surface-associated NgR1 and other related receptors in the brain. We will then ascertain whether this decrease correlates with a reduction in the Nogo-A inhibitory pathway as well as with an increase in cAMP, axonal growth, BDNF, neuroplasticity, and functional recovery as assessed by behavioral studies. We will determine whether the approach of using EGCG (which blocks axonal growth inhibitors as well as potentiates neurotrophins) can be as efficient as or even more efficient than the NgR1 antagonistic peptide NEP1-40 (intranasal delivery to the brain). The successful outcome of this preclinical exploration may prove that the internalization of cell-surface NgR1, induced by EGCG or other agents, desensitizes neurons to axonal growth inhibitors.

项目摘要/摘要中风是造成残疾的主要原因和死亡的主要原因。慢性中风疗法需要通过克服轴突生长抑制剂（如Nogo-A）的功能恢复。虽然正在吸毒目前，没有临床证明的药物可以从中风和其他神经元损伤中恢复。评估安全，神经保护性，神经增生和廉价的天然产品的效率会补充正在进行的努力。缺血性损伤后，常规的轴突生长增强了 “外部”阻断轴突生长抑制剂的方法。我们的假设是轴突生长也可以是通过“本质上”降低神经元对轴突生长抑制剂的敏感性而实现。结合这个神经营养活性的内在方法可能更有效。在低纳摩尔浓度下，绿茶多酚，例如epigallocatechin-3-gallate（EGCG），提升了营地EPAC（交换蛋白质直接被CAMP）途径直接激活，并诱导Nogo-A受体（NGR1）和其他相关接收器。 EGCG因此不仅阻止了Nogo-A的动作，还可以阻止轴突生长的动作抑制剂。同时，EGCG还激活活性氧（ROS） - 蛋白酶激酶CE途径并潜入神经营养蛋白的作用，例如脑衍生的神经营养因子（BDNF）。 EGCG（神经元脱敏对轴突生长抑制剂的脱敏和潜力神经营养蛋白）导致长轴突生长和功能恢复，这可能会用于慢性中风治疗。在第一个目标中，我们将使用原发性皮质神经元来确定EGCG诱导的营地是否是否 EPAC途径可能会导致NGR1及其共感受器的内在化和降解以及其他相关的接收者。我们将确定这是否与EGCG诱导的Nogo-A作用减少有关和其他轴突生长抑制剂。我们还将确定EGCG诱导的ROS-的平行激活是否存在 PKCE途径可以潜在神经营养蛋白（例如BDNF）的作用，并增强长神经蛋白的生长。在第二个目标中，我们将使用MCAO的小鼠模型（中大脑动脉闭塞/再灌注）诱导中风。对于慢性中风疗法，我们每天将通过饮酒每天管理一定剂量的EGCG 水。我们将确定EGCG是否降低了与神经元相关的NGR1和其他相关的降低大脑中的接收器。然后，我们将确定这种减少是否与Nogo-A的减少相关抑制途径以及营地，轴突生长，BDNF，神经可塑性和功能的增加通过行为研究评估的恢复。我们将确定是否使用EGCG的方法（哪个阻断轴突生长抑制剂以及潜在的神经营养蛋白）可能会高效甚至更高比NGR1拮抗肽NEP1-40（鼻内递送到大脑）有效。成功这种临床前探索的结果可能证明，细胞表面NGR1的内在化是由 EGCG或其他药物使神经元脱敏，对轴突生长抑制剂。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cyclic adenosine monophosphate-elevating agents inhibit amyloid-beta internalization and neurotoxicity: their action in Alzheimer's disease prevention.

DOI：
10.4103/1673-5374.373664
发表时间：
2023-12
期刊：
Neural regeneration research
影响因子：
6.1
作者：
Gopalakrishna R;Oh A;Bhat NR;Mack WJ
通讯作者：
Mack WJ

Imbalance in Protein Thiol Redox Regulation and Cancer-Preventive Efficacy of Selenium.

DOI：
10.20455/ros.2016.851
发表时间：
2016
期刊：
Reactive oxygen species (Apex, N.C.)
影响因子：
0
作者：
Gopalakrishna R;Gundimeda U;Zhou S;Zung K;Forell K;Holmgren A
通讯作者：
Holmgren A

Nogo-A receptor internalization by cyclic adenosine monophosphate in overcoming axonal growth inhibitors after stroke.

DOI：
10.4103/1673-5374.314298
发表时间：
2022-01
期刊：
Neural regeneration research
影响因子：
6.1
作者：
Gopalakrishna R;Lin C;Kindy MS;Mack WJ
通讯作者：
Mack WJ

cAMP-induced decrease in cell-surface laminin receptor and cellular prion protein attenuates amyloid-β uptake and amyloid-β-induced neuronal cell death.

cAMP 诱导的细胞表面层粘连蛋白受体和细胞朊病毒蛋白的减少减弱了淀粉样蛋白 β 的摄取和淀粉样蛋白 β 诱导的神经元细胞死亡。

DOI：
10.1002/1873-3468.14467
发表时间：
2022-11
期刊：
FEBS LETTERS
影响因子：
3.5
作者：
Gopalakrishna, Rayudu;Lin, Charlotte Y.;Oh, Andrew;Le, Calvin;Yang, Seolyn;Hicks, Alexandra;Kindy, Mark S.;Mack, William J.;Bhat, Narayan R.
通讯作者：
Bhat, Narayan R.