BACE1 inhibition in injured peripheral nerve and a neuropathy mouse models

BACE1 抑制损伤周围神经和神经病小鼠模型

基本信息

批准号：
9041692
负责人：
Mohamed H Farah
金额：
$ 35.44万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9041692
关键词：
Alzheimer&apos s Disease Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Animals Aspartic Endopeptidases Atrophic Axon Biological C-terminal Cell Culture Techniques Cell surface Cessation of life Chemotherapy-induced peripheral neuropathy Cleaved cell Complement Crush Injury Data Dependovirus Disease Distal Electrophysiology (science)Environment Enzymes Evaluation Excision Exhibits Experimental Models Gene Delivery Genetic Grant Growth Health Human Inflammation Knock-out Knockout Mice Lead Lumbar spinal cord structure Mediating Membrane Membrane Proteins Modeling Molecular Mus Myelin N-terminal Natural regeneration Nerve Nerve Crush Nerve Regeneration Neurites Neurologic Neurons Neuropathy Pathway interactions Peripheral Peripheral Nerves Peripheral Nervous System Diseases Peripheral nerve injury Phagocytosis Pharmaceutical Preparations Physiological Proteins Proteolysis Recovery Recovery of Function Regulation Risk Rodent Rodent Model Schwann Cells Sensory Signal Transduction Speed Spinal Ganglia TNF gene TNFRSF1A gene Testing Therapeutic Tissues amyloid precursor protein processing axon regeneration axonal degeneration base behavioral study beta-site APP cleaving enzyme 1 chemotherapy induced neuropathy cytokine effective therapy functional restoration genetic manipulation improved in vivo inhibitor/antagonist injured macrophage mouse model nerve injury peripheral nerve regeneration pre-clinical receptor reinnervation sciatic nerve small molecule

项目摘要

DESCRIPTION (provided by applicant): Peripheral nerve damage and diseases are common health problems that often result in long-term functional deficits. Peripheral axons can regenerate and reinnervate target tissue following nerve injury or disease in young rodent animals. However, human axonal regeneration is very slow and both denervated Schwann cells, which provide a permissive micro-environment for regeneration, and target tissues are at risk for undergoing atrophy and death, precluding functional recover. This situation underscores the critical need for agents that can speed up axonal regeneration to restore function. A prime candidate for enhancing axonal regeneration is inhibition of Beta -Amyloid Cleaving Enzyme (BACE1). Recently, we show that genetic deletion and pharmacological inhibition of BACE1 markedly accelerate axonal regeneration in the injured peripheral nerves of mice. However, it is unclear how inhibition of BACE1 improves nerve regeneration. We postulate that accelerated nerve regeneration is due to blockade of BACE1 cleavage of two different BACE1 substrates. The two proposed substrates are the amyloid precursor protein (APP) in axons and tumor necrosis factor receptor 1 (TNFR1) on macrophages, which infiltrate injured nerves and clear the inhibitory myelin debris. We will systematically explore genetic manipulations of these two substrates in regard to accelerated axonal regeneration and rapid myelin debris removal seen in BACE1 KO mice. Equally importantly, we propose critical evaluations of a new and very attractive therapeutic approach (e.g. pharmacological inhibition of BACE1) to accelerate nerve regeneration in preclinical rodent models. As experimental models, we will employ peripheral nerve injury and chemotherapy-induced peripheral neuropathy in mice. To evaluate BACE1 inhibitors as a therapy for nerve damage and chemotherapy-induced peripheral neuropathy, we plan to take combined approaches of morphological, electrophysiological and behavioral studies. The proposed studies are highly relevant because faster rate of outgrowth associated with BACE1 inhibition could be useful in speeding nerve regeneration in human conditions.

描述（由申请人提供）：周围神经损害和疾病是常见的健康问题，通常会导致长期功能缺陷。外周轴突可以在幼啮齿动物的神经损伤或疾病后再生并重新弥补目标组织。然而，人轴突再生非常缓慢，两个无用的雪旺细胞，可为再生提供宽松的微环境，靶组织有萎缩和死亡的风险，排除了功能恢复。这种情况强调了对可以加快轴突再生以恢复功能的代理的关键需求。增强轴突再生的主要候选者是抑制β淀粉样蛋白切割酶（BACE1）的抑制作用。最近，我们表明，遗传缺失和药理学抑制BACE1在损伤的小鼠外周神经中显着加速了轴突再生。但是，尚不清楚BACE1的抑制如何改善神经再生。我们假设，加速的神经再生是由于两种不同BACE1底物的BACE1裂解的阻断而导致的。所提出的两个底物是轴突中的淀粉样蛋白前体蛋白（APP），巨噬细胞上的肿瘤坏死因子受体1（TNFR1），它们浸润神经并清除抑制性髓磷脂碎屑。我们将系统地探索这两种底物的遗传操纵，以在BACE1 KO小鼠中观察到的加速轴突再生和快速的髓磷脂碎屑去除。同样重要的是，我们提出了对一种新的且非常有吸引力的治疗方法（例如，BACE1的药理抑制）的批判性评估，以加速临床前啮齿动物模型中的神经再生。作为实验模型，我们将采用外周神经损伤和化学疗法诱导的小鼠周围神经病。为了评估BACE1抑制剂作为神经损伤和化学疗法引起的周围神经病的一种疗法，我们计划采取形态学，电生理和行为研究的联合方法。拟议的研究高度相关，因为与BACE1抑制相关的生长速度更快，对于在人类条件下的神经再生可能很有用。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sensory and autonomic function and structure in footpads of a diabetic mouse model.

DOI：
10.1038/srep41401
发表时间：
2017-01-27
期刊：
Scientific reports
影响因子：
4.6
作者：
Liu Y;Sebastian B;Liu B;Zhang Y;Fissel JA;Pan B;Polydefkis M;Farah MH
通讯作者：
Farah MH

Beta secretase activity in peripheral nerve regeneration.

DOI：
10.4103/1673-5374.217319
发表时间：
2017-10
期刊：
Neural regeneration research
影响因子：
6.1
作者：
Tallon C;Farah MH
通讯作者：
Farah MH

Length-dependent axo-terminal degeneration at the neuromuscular synapses of type II muscle in SOD1 mice.

DOI：
10.1016/j.neuroscience.2015.11.018
发表时间：
2016-01-15
期刊：
Neuroscience
影响因子：
3.3
作者：
Tallon C;Russell KA;Sakhalkar S;Andrapallayal N;Farah MH
通讯作者：
Farah MH

The influence of BACE1 on macrophage recruitment and activity in the injured peripheral nerve.

DOI：
10.1186/s12974-021-02121-2
发表时间：
2021-03-15
期刊：
Journal of neuroinflammation
影响因子：
9.3
作者：
Fissel JA;Farah MH
通讯作者：
Farah MH

Pharmacological BACE Inhibition Improves Axonal Regeneration in Nerve Injury and Disease Models.

药理学 BACE 抑制可改善神经损伤和疾病模型中的轴突再生。

DOI：
10.1007/s13311-020-00852-3
发表时间：
2020
期刊：
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
影响因子：
0
作者：
Tallon,Carolyn;Marshall,KatherineL;Kennedy,MatthewE;Hyde,LynnA;Farah,MohamedH
通讯作者：
Farah,MohamedH