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：
8640221
负责人：
Mohamed H Farah
金额：
$ 35.08万
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 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8640221
关键词：
Alzheimer&apos s Disease Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Animals Aspartic Endopeptidases Atrophic Axon Behavioral Biological C-terminal Cell Culture Techniques Cell surface Cessation of life Cleaved cell Complement Crush Injury Data Dependovirus Disease Distal 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 Testing Therapeutic Tissues Tumor Necrosis Factor Receptor amyloid precursor protein processing axon regeneration axonal degeneration base beta-site APP cleaving enzyme 1 chemotherapy chemotherapy induced neuropathy cytokine effective therapy functional restoration genetic manipulation improved in vivo inhibitor/antagonist injured macrophage mouse model nerve injury 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）：周围神经损伤和疾病是常见的健康问题，通常会导致长期的功能缺陷。幼年啮齿动物神经损伤或疾病后，外周轴突可以再生并重新支配目标组织。然而，人类轴突再生非常缓慢，失神经的雪旺细胞（为再生提供良好的微环境）和靶组织都面临萎缩和死亡的风险，从而妨碍功能恢复。这种情况强调了对能够加速轴突再生以恢复功能的药物的迫切需求。增强轴突再生的主要候选者是抑制β-淀粉样蛋白裂解酶（BACE1）。最近，我们发现 BACE1 的基因缺失和药物抑制可显着加速小鼠受损周围神经的轴突再生。然而，尚不清楚抑制 BACE1 如何改善神经再生。我们推测神经再生加速是由于两种不同 BACE1 底物的 BACE1 裂解被阻断。两种拟议的底物是轴突中的淀粉样蛋白前体蛋白 (APP) 和巨噬细胞上的肿瘤坏死因子受体 1 (TNFR1)，它们会渗透受伤的神经并清除抑制性髓鞘碎片。我们将系统地探索这两种底物的基因操作，以加速 BACE1 KO 小鼠的轴突再生和快速髓磷脂碎片去除。同样重要的是，我们建议对一种新的、非常有吸引力的治疗方法（例如 BACE1 的药理抑制）进行严格评估，以加速临床前啮齿动物模型中的神经再生。作为实验模型，我们将采用小鼠周围神经损伤和化疗引起的周围神经病变。为了评估 BACE1 抑制剂对神经损伤和化疗引起的周围神经病变的治疗作用，我们计划采取形态学、电生理学和行为学研究的结合方法。拟议的研究具有高度相关性，因为与 BACE1 抑制相关的更快的生长速度可能有助于加速人类神经再生。