Development of neuroprotective PDZ-domain inhibitors for the treatment of MS

开发用于治疗 MS 的神经保护性 PDZ 结构域抑制剂

• 批准号: 7531711
• 负责人: JOHN MARSHALL
• 金额: $ 23.46万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531711
• 关键词: AMPA Receptors; Affect; Affinity; Animal Model; Animals; Apoptosis; Attenuated; Binding; Biochemical; Cell Death; Cell Death Signaling Process; Cessation of life; Clinical; Cyclic Peptides; DLG4 gene; Demyelinating Diseases; Demyelinations; Development; Disease; Encephalomyelitis; Experimental Autoimmune Encephalomyelitis; Experimental Models; Glutamate Receptor; Goals; Image; In Vitro; Inflammation; Inflammatory; Link; MAPK8 gene; Measures; Mediating; Modeling; Molecular; Molecular Target; Multiple Sclerosis; N-Methylaspartate; Nerve; Nerve Degeneration; Nerve Fibers; Neurologic; Neurons; Oligodendroglia; Optic Nerve; Optics; Pathology; Pathway interactions; Pharmaceutical Preparations; Play; Production; Property; Public Health; Rattus; Research; Research Project Grants; Retinal; Role; Series; Severities; Signal Pathway; Signal Transduction; Signaling Protein; Spinal Cord; Spinal Cord Tract; Symptoms; Testing; Toxic effect; Work; calmodulin-dependent protein kinase II; clinically relevant; disability; excitotoxicity; improved; in vivo; inhibitor/antagonist; kainate; neuron loss; neuroprotection; novel; novel therapeutics; oligodendrocyte-myelin glycoprotein; postsynaptic density protein; presynaptic density protein 95; prevent; programs; protective effect; retinal neuron; scaffold; scale up

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is characterized by immunological and inflammatory changes that contribute to demyelination of nerve fibers and neuronal cell death. Although MS is a prototypic primary demyelinating disease, increasing evidence indicates that neuronal degeneration also occurs in MS, contributing to the acquisition of nonremitting clinical deficits. The main features of MS can be reproduced in an animal model, experimental autoimmune encephalomyelitis (EAE). Drugs that reduce the activity of the NMDA or Kainate subtypes of glutamate receptors (NMDAR, KAR), which are expressed both on neurons and oligodendrocytes, suppress EAE. In this proposal, a novel cyclic peptide compound, CN2097, will be tested for its ability to ameliorate MS-like symptoms and pathology. This compound binds the PDZ-domain of the postsynaptic density protein, PSD-95, disrupting its interaction with KAR and NMDAR subtypes. PSD-95 plays a critical role in kainate-mediated excitotoxicity by acting as a molecular scaffold to link KARs to JNK activation. NMDA-induced cell death is linked to the association of PSD-95 with CaMKII, nNos and other primary cell death signaling proteins. In an in vivo retinal toxicity model CN2097 completely blocked NMDA-induced cell death. Aim 1 will examine the signaling pathways and the effects of this compound on attenuating kainate-induced cell death in an in vivo retinal toxicity model, as well as in cortical neurons and retinal oligodendrocytes in vitro. Aim 2 will determine whether CN2097 can increase the survival and function of optic and spinal cord nerves using a MS animal model, myelin oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis (MOG-EAE), that emulates MS. Testing the neuroprotective effects of CN2097 in EAE rats is of clinical relevance in slowing or reversing MS-related neurological disability. We hypothesize that this PDZ-domain inhibitor will improve the tolerance for the treatment because it does not appear to interfere with normal NMDA or AMPA receptor activity, while ameliorating the disease related excitotoxic damage. PUBLIC HEALTH RELEVANCE: Recent studies show that glutamate receptors, which are important in transmitting signals from one nerve cell to another, also increase sensitivity to the death of neurons and myelinating oligodendrocytes in multiple sclerosis. We have synthesized a series of high affinity compounds that completely prevent neuronal death and are predicted to improve the tolerance for treatment because they do not affect the ability of glutamate receptors to signal between nerves, while preventing the disease related damage. The central goal of this research grant is to better understand the action of our most promising compound (CN2097) and to determine its potential as a new therapeutic approach for treating multiple sclerosis.

描述（由申请人提供）：多发性硬化症（MS）的特征是免疫和炎症变化，导致神经纤维脱髓鞘和神经元细胞死亡。虽然MS是一种典型的原发性脱髓鞘疾病，但越来越多的证据表明MS中也发生神经元变性，导致获得非缓解性临床缺陷。MS的主要特征可以在实验性自身免疫性脑脊髓炎（EAE）动物模型中再现。降低谷氨酸受体的NMDA或红藻氨酸盐亚型（NMDAR，KAR）活性的药物抑制EAE，这些受体在神经元和少突胶质细胞上表达。在该提案中，将测试新型环肽化合物CN 2097改善MS样症状和病理的能力。该化合物结合突触后密度蛋白PSD-95的PDZ结构域，破坏其与KAR和NMDAR亚型的相互作用。PSD-95在红藻氨酸介导的兴奋性毒性中起关键作用，其作为分子支架将KAR与JNK活化连接起来。NMDA诱导的细胞死亡与PSD-95与CaMKII、nNos和其他主要细胞死亡信号传导蛋白的缔合有关。在体内视网膜毒性模型中，CN 2097完全阻断NMDA诱导的细胞死亡。目的1将检查信号通路和这种化合物在体内视网膜毒性模型中以及在体外皮质神经元和视网膜少突胶质细胞中对衰减红藻氨酸诱导的细胞死亡的影响。目的2将使用模拟MS的MS动物模型（髓鞘少突胶质细胞糖蛋白-实验性自身免疫性脑脊髓炎（MOG-EAE））来确定CN 2097是否可以增加视神经和脊髓神经的存活和功能。在EAE大鼠中测试CN 2097的神经保护作用在减缓或逆转MS相关的神经功能障碍方面具有临床意义。我们假设这种PDZ结构域抑制剂将改善对治疗的耐受性，因为它似乎不干扰正常的NMDA或AMPA受体活性，同时改善疾病相关的兴奋性毒性损伤。公共卫生关系：最近的研究表明，谷氨酸受体，这是重要的信号从一个神经细胞到另一个，也增加了敏感性神经元和髓鞘少突胶质细胞在多发性硬化症的死亡。我们已经合成了一系列高亲和力化合物，其完全防止神经元死亡，并且被预测为改善对治疗的耐受性，因为它们不影响谷氨酸受体在神经之间传递信号的能力，同时防止疾病相关的损伤。这项研究资助的中心目标是更好地了解我们最有前途的化合物（CN 2097）的作用，并确定其作为治疗多发性硬化症的新治疗方法的潜力。