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

• 批准号: 8481608
• 负责人: Mohamed H Farah
• 金额: $ 34.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/8481608
• 关键词: Alzheimer' 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; 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

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(申请人提供)：周围神经损伤和疾病是常见的健康问题，经常导致长期的功能缺陷。在幼年啮齿动物的神经损伤或疾病后，外周轴突可以再生和重新支配靶组织。然而，人的轴突再生非常缓慢，失神经的雪旺细胞为再生提供了一个允许的微环境，靶组织面临萎缩和死亡的风险，阻碍了功能的恢复。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要。抑制β-淀粉样蛋白裂解酶(BACE1)是促进轴突再生的首选方法。最近，我们发现BACE1的基因缺失和药物抑制显著促进了小鼠受损周围神经的轴突再生。然而，目前尚不清楚抑制BACE1如何促进神经再生。我们推测，神经再生的加速是由于阻断了两种不同的BACE1底物的BACE1裂解。提出的两种底物是轴突中的淀粉样前体蛋白(APP)和巨噬细胞上的肿瘤坏死因子受体1(TNFR1)，它们渗透到受损的神经中，清除抑制的髓鞘碎片。我们将系统地探索这两种底物在BACE1 KO小鼠中关于加速轴突再生和快速去除髓鞘碎片的遗传操作。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的药物抑制)进行批判性评估，以加速临床前啮齿动物模型的神经再生。作为实验模型，我们将采用周围神经损伤和化疗诱导的小鼠周围神经病变。为了评价BACE1抑制剂对神经损伤和化疗所致周围神经病的治疗作用，我们计划采取形态学、电生理和行为研究相结合的方法。这项拟议的研究具有很高的相关性，因为与抑制BACE1相关的更快的生长速度可能有助于加速人类条件下的神经再生。