The Effect of a Nerve Growth Factor Mimetic in Demyelination and Remyelination

神经生长因子模拟物在脱髓鞘和髓鞘再生中的作用

• 批准号: 7502085
• 负责人: GLENN K. MATSUSHIMA
• 金额: $ 17.99万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7502085
• 关键词: Adverse effects; Animals; Apoptosis; Apoptotic; Astrocytes; Axon; Blood - brain barrier anatomy; Brain; C57BL/6 Mouse; Cell Death; Cell Maturation; Cell Survival; Cell physiology; Cessation of life; Chronic; Clinical; Corpus Callosum; Cultured Cells; Cuprizone; Data; Demyelinating Diseases; Demyelinations; Development; Disease Progression; Dose; Environmental Risk Factor; Event; Exposure to; Fibrinogen; Gender; Genetic Predisposition to Disease; Immune; Immunohistochemistry; Implant; In Vitro; Intoxication; Laboratories; Lesion; Ligands; Link; Longitudinal Studies; Mediating; Microglia; Modeling; Molecular; Molecular Profiling; Multiple Sclerosis; Mus; Myelin; NGFR Protein; Nerve Growth Factors; Neuraxis; Neuroglia; Neurons; Oligodendroglia; Pathology; Pattern; Personal Satisfaction; Plasma; Population; Proteins; Pump; Rate; Receptor Protein-Tyrosine Kinases; Role; Signal Transduction; Therapeutic; Therapeutic Agents; Thinking; Time; Titrations; Toxic effect; Virus; Week; Work; base; cell type; central nervous system demyelinating disorder; design; dosage; human disease; in vivo; insight; macrophage; mimetics; myelination; nervous system disorder; neuron loss; neurotrophic factor; novel; novel therapeutics; oligodendrocyte precursor; precursor cell; prevent; receptor; small molecule

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic, unpredictable neurological disease of the central nervous system (CNS) and may be caused by more than one factor, such as genetic predisposition, gender, environmental factors, and exposure to seemingly innocuous viruses. Pharmacologic therapies targeting CNS demyelinating diseases such as MS have been sparse and mostly act by broad-spectrum immune suppression of which the mechanisms of actions are not completely understood. Recent studies have brought small molecule mimetics (SMMs) that emulate functional protein ligand-receptor interactions to the fore in potential therapeutic development. Our laboratory will use an SMM of nerve growth factor (NGF), namely C31 or LM11A-31, as a therapeutic agent to alter CNS demyelination and/or remyelination. NGF is well known for its trophic role in neuronal and glial cell survival and differentiation in the CNS via tyrosine receptor kinase A (TrkA). However, NGF, unlike other neurotrophins, also has the ability to induce apoptosis in its precursor form, proNGF, through the p75 neurotrophin receptor (p75NTR). C31, which is comprised of residues of the 2-loop 1 domain of NGF, interacts with p75NTR. Previous studies show NGF Loop 1 mimetics provide in vitro protection against neuronal cell death via p75NTR-dependent signaling and also afforded protection of mature oligodendrocytes (OLs) from cell death in the presence of proNGF, presumably by initiating pro-survival signaling. To further study the effect of C31 in vivo, our laboratory will use the cuprizone intoxication model in which changes in cellular populations and myelination are both reproducible and predictable in the corpus callosum of a C57BL/6 mouse. Although p75NTR is mainly expressed during early neuronal development, we have preliminary data that re-expression of p75NTR can be detected by immunohistochemistry in the demyelinating corpus callosum. Using our cuprizone intoxication model of demyelination and remyelination, we hypothesize that C31 protects OLs in vivo. We predict this may prevent or delay demyelination or increase the rate of remyelination. The specific aims of this proposal are designed to demonstrate the effects of C31 on the cellular, molecular, and morphologic profiles during demyelination/remyelination, and to eventually link the expression profile of p75NTR to the mechanism of C31 action. If administration of C31 hinders disease progression, then this may provide insights to feasibility and mechanism of SMM with potential therapeutic ramifications for demyelinating diseases. This proposal explores the feasibility of a potential novel therapeutic compound, C31 that mimics a fragment of nerve growth factor, to ameliorate central nervous system demyelination. C31 has been shown to protect oligodendrocytes in vitro and examination of its function in vivo is warranted. If this proposal provides evidence that C31 ameliorates CNS pathology, then there is a potential to move C31 towards clinical considerations for the eventual application to human diseases such as multiple sclerosis.

描述（由申请人提供）：多发性硬化症（MS）是一种慢性、不可预测的中枢神经系统（CNS）神经系统疾病，可能由多种因素引起，如遗传易感性、性别、环境因素和暴露于看似无害的病毒。靶向CNS脱髓鞘疾病（如MS）的药物治疗很少，主要通过广谱免疫抑制发挥作用，其作用机制尚未完全了解。最近的研究使模拟功能性蛋白质配体-受体相互作用的小分子模拟物（SMM）在潜在的治疗开发中脱颖而出。我们的实验室将使用神经生长因子（NGF）的SMM，即C31或LM11A-31，作为改变CNS脱髓鞘和/或髓鞘再生的治疗剂。众所周知，NGF通过酪氨酸受体激酶A（TrkA）在CNS中的神经元和神经胶质细胞存活和分化中起营养作用。然而，与其他神经营养因子不同，NGF也具有通过p75神经营养因子受体（p75NTR）以其前体形式proNGF诱导细胞凋亡的能力。C31由NGF的2-环1结构域的残基组成，与p75NTR相互作用。先前的研究表明，NGF环1模拟物通过p75NTR依赖性信号传导提供体外保护以对抗神经元细胞死亡，并且还在proNGF存在下提供成熟少突胶质细胞（OL）免于细胞死亡的保护，推测是通过启动促存活信号传导。为了进一步研究C31在体内的作用，我们的实验室将使用cuprizone中毒模型，其中细胞群体和髓鞘形成的变化在C57BL/6小鼠的胼胝体中是可再现和可预测的。虽然p75 NTR主要在早期神经元发育过程中表达，但我们有初步数据表明，在脱髓鞘胼胝体中，p75 NTR的再表达可以通过免疫组化检测到。使用我们的脱髓鞘和髓鞘再生的铜腙中毒模型，我们假设C31在体内保护OL。我们预测这可能会阻止或延迟脱髓鞘或增加髓鞘再生的速度。该提案的具体目的是证明C31对脱髓鞘/髓鞘再生过程中细胞、分子和形态学特征的影响，并最终将p75 NTR的表达谱与C31作用机制联系起来。如果C31的施用阻碍疾病进展，则这可能为SMM的可行性和机制提供见解，具有脱髓鞘疾病的潜在治疗分支。该提案探讨了一种潜在的新型治疗化合物C31的可行性，该化合物模拟神经生长因子的片段，以改善中枢神经系统脱髓鞘。C31已被证明可以在体外保护少突胶质细胞，因此有必要在体内检查其功能。如果这项提议提供了C31改善CNS病理的证据，那么有可能将C31推向临床考虑，最终应用于人类疾病，如多发性硬化症。