Remyelination by intranasal TIDM peptide

鼻内 TIDM 肽进行髓鞘再生

• 批准号: 10582863
• 负责人: KALIPADA PAHAN
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582863
• 关键词: Air Pollutants; Animal Model; Anthrax disease; Area; Autoimmunity; Axon; Bacteria; Binding; CD4 Positive T Lymphocytes; Caucasians; Cell Maturation; Cell Separation; Cells; Central Nervous System; Central Nervous System Viral Diseases; Chemicals; Chronic; Cuprizone; Demyelinating Diseases; Demyelinations; Diagnosis; Dissociation; Endowment; Engineering; Etiology; European ancestry; Experimental Autoimmune Encephalomyelitis; Exposure to; Flagellin; Genes; Genetic; Gulf War; Hepatitis B; Human; Immune; Incidence; Inflammation; Injury; Innate Immune System; Intoxication; Intranasal Administration; Investments; Knockout Mice; Lesion; Link; Mediating; Microglia; Modeling; Monitor; Multiple Sclerosis; Mus; Mutate; Myelin; Natural Immunity; Neurology; Oligodendroglia; Outcome; Pathogenesis; Peptides; Persons; Play; Proliferating; Research; Risk; Role; Services; Signal Transduction; Specificity; T-Lymphocyte; TLR2 gene; Testing; Therapeutic; Toll-like receptors; Toxin; United States; Vaccination; Veterans; Vietnam; Viral; Virus; Virus Diseases; War; Wild Type Mouse; adaptive immunity; central nervous system demyelinating disorder; combat; design; effective therapy; experimental study; glial activation; in vivo; in vivo Model; inhibitor; knock-down; member; multiple sclerosis patient; new technology; novel; oligodendrocyte myelination; prospective; remyelination; response; stem cells

Multiple sclerosis (MS) is the most common human demyelinating disorder of the central nervous system (CNS). Although the etiology of MS is unknown, it is connected to autoimmunity. At present, about 400,000 people in the United States have MS. It is more prevalent among Caucasians, particularly those of northern European ancestry, than others. Several evidences also show a potential link between the incidence of MS and combat service. For example, one study in the Annals of Neurology (2004, 55: 65-71) has identified 5,345 cases of MS among U.S. veterans that were considered "service-connected." Although the mechanism is not clear, viral infections, several vaccinations and/or exposure to different war zone chemicals may increase the risk of having MS. Accordingly, several veterans who served Gulf war 1 as well as many Vietnam veterans have been diagnosed with MS. Although there are some therapies against MS, no effective therapy is available to promote remyelination in MS. Therefore, delineation of new technologies for promoting remyelination is an important area of research. Oligodendrocytes (OLs) are the myelin-producing cells in the CNS and toll-like receptor 2 (TLR2) is an important member of innate immunity. It has been shown that TLR2 activation inhibits the maturation of oligodendroglial progenitor cells (OPCs). Since there was no specific inhibitor of TLR2, from structural analysis of the interaction between TLR2 and MyD88, the downstream partner of TLR2, we have designed a novel peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that specifically blocks TLR2, but not other TLRs. Therefore, here, we want to test a translational, but novel, hypothesis that wtTIDM peptide stimulates the maturation of OPCs to OLs (Specific aim I) and that intranasal administration of wtTIDM peptide stimulates remyelination in animal models of demyelination (Specific aim II) via microglial and/or OPC TLR2 (Specific aim III). A positive outcome of this cutting-edge proposal will delineate if selective targeting of activated status of one component (TLR2) of the innate immune system by wtTIDM peptide increases the maturation of OPCs and stimulates remyelination, highlighting the discovery of a prospective intranasal agent to promote remyelination in MS and other demyelinating disorders.

多发性硬化症（MS）是人类最常见的中枢神经系统脱髓鞘疾病 （中枢神经系统）。尽管多发性硬化症的病因尚不清楚，但它与自身免疫有关。目前，约有40万 美国人患有多发性硬化症。它在白种人中更为普遍，尤其是北方人 欧洲血统，比其他人。一些证据还表明 MS 的发病率与 战斗服务。例如，《神经病学年鉴》(Annals of Neurology) (2004, 55: 65-71) 中的一项研究已确定 5,345 美国退伍军人中被认为“与服役有关”的多发性硬化症病例。虽然机制不 明确的病毒感染、多次疫苗接种和/或接触不同战区化学品可能会增加 患多发性硬化症的风险。因此，几名参加过第一次海湾战争的退伍军人以及许多越南退伍军人 被诊断患有多发性硬化症。尽管有一些针对多发性硬化症的治疗方法，但尚无有效的治疗方法 促进多发性硬化症的髓鞘再生。 因此，开发促进髓鞘再生的新技术是一个重要的研究领域。 少突胶质细胞 (OL) 是中枢神经系统中产生髓磷脂的细胞，Toll 样受体 2 (TLR2) 是一种 先天免疫的重要成员。研究表明，TLR2 的激活会抑制 TLR2 的成熟。 少突胶质祖细胞（OPC）。由于TLR2尚无特异性抑制剂，从结构上看 分析TLR2和TLR2下游伙伴MyD88之间的相互作用，我们设计了一个 与 MyD88 (TIDM) 的 TLR2 相互作用结构域相对应的新型肽，可特异性阻断 TLR2， 但其他 TLR 则不然。因此，在这里，我们想要测试一个新颖的转化假设，即 wtTIDM 肽刺激 OPC 成熟为 OL（具体目标 I），并且鼻内给药 wtTIDM 肽通过小胶质细胞刺激脱髓鞘动物模型（特定目标 II）的髓鞘再生 和/或 OPC TLR2（具体目标 III）。如果有选择的话，这一前沿提案将取得积极成果 通过 wtTIDM 肽靶向先天免疫系统的一种成分 (TLR2) 的激活状态 增加 OPC 的成熟并刺激髓鞘再生，突出显示了一种潜在的发现 鼻内药物，促进多发性硬化症和其他脱髓鞘疾病的髓鞘再生。