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The molecular mechanism and therapeutics in axon regeneration

轴突再生的分子机制和治疗方法

基本信息

批准号：
10208978
负责人：
Arthur W. English
金额：
$ 34.13万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208978
关键词：
Adult Affect Agonist Alzheimer&apos s disease brain Asparagine Axon Biological Assay Biological Availability Brain-Derived Neurotrophic Factor Caspase Cleaved cell Cytoskeleton Data Distal Elements Endopeptidases Exhibits Foundations Goals Growth Growth Factor Half-Life Human In Vitro Individual Injury Knock-out Knockout Mice Knowledge Ligands Light MAP Kinase Gene MAPT gene Mediating Medical Microtubule Stabilization Microtubules Molecular Mus Muscle Fibers Natural regeneration Neurites Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Oral Oral Administration PF4 Gene Pathologic Peripheral Nerves Peripheral nerve injury Pharmacology Phosphorylation Plasma Play Polymers Process Prodrugs Protease Inhibitor Recovery Recovery of Function Role Signal Transduction Spinal Ganglia Testing Therapeutic Therapeutic Effect Treatment Efficacy Treatment Factor alpha Tubulin asparaginylendopeptidase axon growth axon injury axon regeneration beta Tubulin design disability burden drug development endopeptidase A experimental study in vivo inhibitor/antagonist insight mimetics monomer mutant nerve injury nervous system disorder neurotrophin 4 new therapeutic target novel novel strategies novel therapeutics polymerization prevent regeneration following injury regenerative restoration secretase small molecule targeted treatment tau Proteins therapeutic evaluation treatment effect

项目摘要

Summary Injuries to peripheral nerves are common, but recovery from them is very poor. There is currently no non- surgical treatment available. Brain-derived neurotrophic factor (BDNF), and other growth factors, are known to promote axon regeneration following peripheral nerve injury. The objectives of this proposal are to: 1) investigate whether the molecular mechanism by which this effect is achieved is through stabilization of the axonal microtubule-associated protein, Tau in the regenerating axons; and 2) to examine the therapeutic efficacy of two targeted pharmacological agents designed to mimic these cellular effects. Asparagine endopeptidase (AEP), a cysteine protease, is robustly activated in cut peripheral nerves and mediates cleavage of Tau that degrades its stabilizing effect on the axonal cytoskeleton. Because such stabilization is an essential feature of successful axon regeneration after peripheral nerve injury, inhibiting AEP could be an important effect of growth factor signaling after peripheral nerve injury. We hypothesize that Akt, activated by growth factors such as BDNF (or the small molecule BDNF mimetic, 7,8 DHF), phosphorylates AEP and suppresses its enzymatic activity, thereby preventing degradation of Tau, leading to enhanced axon regeneration. We will combine in vitro and in vivo experiments to evaluate critical aspects of this hypothesis in the first two Specific Aims. We have developed a prodrug that elevates oral bioavailability of 7,8-DHF. We also have identified a small allosteric inhibitor of AEP, which blocks Tau cleavage in mice. We will explore the therapeutic efficacy of treatments with the prodrug or/and the AEP inhibitor in promoting axon regeneration and functional recovery in Specific Aim 3. Successful completion of the proposed studies will lead to better understanding of the molecular mechanisms of growth factor-mediated axon regeneration and identification of a novel drug target for treatment of peripheral nerve injury.

总结