Fibronectin peptide antagonism for chronic inflammatory neuropathies

纤连蛋白肽拮抗慢性炎症性神经病

• 批准号: 8240721
• 负责人: Eroboghene Ekamereno Ubogu
• 金额: $ 23.48万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240721
• 关键词: Acute; Address; Adhesions; Adverse effects; Affect; Age; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Process; Behavioral; Binding; Binding Sites; Blood Circulation; Blood capillaries; Blood-Nerve Barrier; Bone Marrow; CS1 peptide; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Chronic; Chronic Inflammatory Demyelinating Polyradiculoneuropathy; Critiques; Data; Demyelinations; Development; Disease; Disease Progression; Dose; Endothelial Cells; Ethnic group; Evaluation; Event; Family; Fibronectins; Goals; Guillain-Barré Syndrome; Healthcare; Healthcare Systems; Hematogenous; Human; Immune; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Lead; Leukocyte Trafficking; Leukocytes; Mediating; Methods; Modeling; Molecular; Mononuclear Leukocytes; Multiple Sclerosis; Mus; Muscle; Nerve; Neuritis; Neuropathy; Paralysed; Pathogenesis; Pathologic; Pathway interactions; Patients; Peptides; Peripheral; Peripheral Nerves; Pharmaceutical Preparations; Phase I Clinical Trials; Plant Roots; Polyneuropathy; Publishing; Recruitment Activity; Renal function; Research; Safety; Signal Transduction; Socioeconomic Status; Study Section; Study models; Syndrome; Techniques; Time; United States; Update; Video Microscopy; Work; Writing; axonal degeneration; base; capillary; care burden; cytokine; disability; improved; in vivo; liver function; meetings; migration; mouse model; novel; painful neuropathy; peripheral blood; pre-clinical; preclinical evaluation; racial and ethnic; research study; sex; tool; trafficking; treatment strategy

DESCRIPTION: Our objective is to evaluate whether inhibition of fibronectin-dependent leukocyte infiltration into peripheral nerves is a specific therapy for chronic peripheral nerve inflammation seen in immune-mediated disorders and neuropathic pain. Using chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as an example of persistent peripheral nerve inflammation that results in significant long-term disability, we propose to address a fundamental question: Is competitive antagonism of fibronectin connecting segment-1 (FN CS1) a potential treatment strategy for peripheral neuritis? Based on our exciting new preliminary data using in vitro and in vivo approaches, we propose the following hypothesis: Endothelial FN CS1 actively participates in the recruitment of pathogenic hematogenous mononuclear leukocytes across the blood-nerve barrier in CIDP. As an extension of this, we propose that competitive inhibition with a FN CS1 peptide antagonist would reduce leukocyte trafficking at the blood-nerve barrier. Reduction in leukocyte infiltration would limit the harmful consequences of prolonged peripheral nerve inflammation, demyelination and axonal injury. This strategy provides an opportunity to develop a novel targeted therapy for CIDP and neuropathic pain. In order to address this hypothesis, we will determine that competitive FN CS1 peptide blockade reduces trafficking of untreated CIDP patient peripheral blood mononuclear leukocytes on a novel cytokine- stimulated human in vitro blood-nerve barrier model that incorporates capillary flow rates. Trafficking events would be captured real-time and quantified by video microscopy. We will also evaluate the effect of this peptide antagonist on the behavioral, electrophysiological and histopathological features of progressive chronic peripheral nerve inflammation, demyelination and axonal injury in a severe, reliable CIDP mouse model, using our published methods. Current therapies for CIDP and other peripheral nerve inflammatory disorders, including neuropathic pain are non-specific and partly effective. This proposal is a preclinical evaluation of FN CS1 peptide antagonism as a targeted anti-inflammatory therapy for CIDP. Inhibiting disease-specific inflammatory pathways has the potential to revolutionize the treatment of chronic peripheral nerve inflammation. The proposed work could lead towards the development of novel, small molecular antagonists for phase I clinical trials in CIDP and other chronic inflammatory neuropathies, as well as neuropathic pain. PUBLIC HEALTH RELEVANCE: The purpose of our work is to discover a new treatment for an under-recognized, but severe disabling nerve inflammation disease called chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). CIDP equally affects both sexes, all ages, racial/ ethnic groups and socioeconomic status. By finding new treatments for CIDP, we can hopefully better treat or cure this problem, improve the lives of patients and their families, and reduce the financial burden of this and similar diseases, such as Guillain-Barri syndrome and neuropathic pain, on the health care system nationally and internationally. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of th individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.

产品说明：我们的目的是评估是否纤连蛋白依赖性白细胞浸润到周围神经的抑制是一种特异性治疗慢性周围神经炎症免疫介导的疾病和神经性疼痛。使用慢性炎症性脱髓鞘性多神经根神经病（CIDP）作为持续性周围神经炎症的例子，导致显着的长期残疾，我们建议解决一个基本的问题：竞争性拮抗纤维连接蛋白连接段1（FN CS 1）周围神经炎的潜在治疗策略？基于我们使用体外和体内方法的令人兴奋的新的初步数据，我们提出以下假设：内皮FN CS 1积极参与CIDP中病原性造血单核白细胞穿过血-神经屏障的募集。作为这一点的延伸，我们提出，竞争性抑制与FN CS 1肽拮抗剂将减少白细胞运输的血神经屏障。减少白细胞浸润将限制有害的 长期的周围神经炎症、脱髓鞘和轴突损伤的后果。这一策略为开发CIDP和神经病理性疼痛的新型靶向治疗提供了机会。为了解决这一假设，我们将确定竞争性FN CS 1肽阻断减少未治疗的CIDP患者外周血单核白细胞在新的细胞因子刺激的人体外血-神经屏障模型上的运输，该模型包含毛细血管流速。贩运活动将通过视频显微镜实时捕捉和量化。我们还将使用我们已发表的方法，在严重、可靠的CIDP小鼠模型中评估这种肽拮抗剂对进行性慢性外周神经炎症、脱髓鞘和轴突损伤的行为、电生理和组织病理学特征的影响。目前用于CIDP和其他周围神经炎性病症（包括神经性疼痛）的疗法是非特异性的并且部分有效。该提案是FN CS 1肽拮抗作用作为CIDP靶向抗炎治疗的临床前评价。抑制疾病特异性炎症通路有可能彻底改变慢性外周神经炎症的治疗。拟议的工作可能会导致开发新的小分子拮抗剂，用于CIDP和其他慢性炎症性神经病以及神经性疼痛的I期临床试验。 公共卫生相关性：我们工作的目的是发现一种新的治疗方法，用于治疗一种未被充分认识但严重致残的神经炎症疾病，称为慢性炎症性脱髓鞘性多神经根神经病（CIDP）。CIDP同样影响到男女、所有年龄、种族/族裔群体和社会经济地位。通过寻找CIDP的新疗法，我们有望更好地治疗或治愈这个问题，改善患者及其家人的生活，并减少 这种疾病和类似疾病，如格林-巴利综合征和神经性疼痛，对国家和国际卫生保健系统的经济负担。 免责声明：请注意，以下评论由审查员在研究部分会议之前准备，并以基本上未经编辑的形式提供。 虽然审查人员有机会根据小组讨论情况更新或修订其书面评价，但不能保证在会议讨论之后更新了个人评论。 因此，评论可能无法完全反映小组讨论结束时个人评论者的最终意见或小组的最终多数意见。因此，讨论的简历和摘要是评审员在会议上实际认为关键的最后一句话。