Fibronectin peptide antagonism for chronic inflammatory neuropathies

描述：我们的目标是评估抑制纤维连接蛋白依赖的白细胞渗透到周围神经是否是免疫介导性疾病和神经病理性疼痛所见的慢性周围神经炎的特异性治疗方法。以慢性炎症性脱髓鞘性多发性神经根神经病(CIDP)为例，我们建议解决一个基本问题：纤维连接蛋白连接段1(FN CS1)的竞争性拮抗是否是治疗周围神经炎的潜在策略？基于我们用体外和体内方法获得的令人兴奋的新的初步数据，我们提出了以下假设：内皮FN CS1积极参与CIDP中病理性血源性单个核细胞跨越血-神经屏障的募集。作为这一点的延伸，我们认为FN CS1肽拮抗剂的竞争性抑制将减少血-神经屏障上的白细胞运输。减少白细胞的渗透将限制有害的 长期周围神经炎症、脱髓鞘和轴突损伤的后果。这一策略为开发一种新的针对CIDP和神经病理性疼痛的靶向疗法提供了机会。为了解决这一假设，我们将确定竞争性FN CS1肽阻断在一个新的细胞因子刺激的人体外血-神经屏障模型上减少未经治疗的CIDP患者外周血单核白细胞的运输，该模型结合了毛细血管流速。贩运活动将被实时捕捉，并通过视频显微镜进行量化。我们还将使用我们发表的方法，评估该肽拮抗剂对严重、可靠的CIDP小鼠模型中进行性慢性周围神经炎症、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。目前对CIDP和包括神经病理性疼痛在内的其他周围神经炎症性疾病的治疗都是非特异性的，部分有效。这项建议是对FN CS1肽拮抗剂作为一种针对CIDP的靶向抗炎治疗的临床前评估。抑制疾病特异性炎症通路有可能彻底改变慢性周围神经炎的治疗方法。拟议的工作可能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病理性疼痛的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，用于治疗一种被称为慢性炎症性脱髓鞘多神经根神经病(CIDP)的未被充分认识但严重致残的神经炎性疾病。儿童保护政策同样影响两性、所有年龄、种族/民族群体和社会经济地位。通过寻找新的治疗方法，我们有望更好地治疗或治愈这一问题，改善患者及其家人的生活，并减少 这一疾病以及类似疾病，如格林-巴利综合征和神经性疼痛，给国家和国际卫生保健系统造成了财政负担。 免责声明：请注意，以下批评是由评审员在研究小组会议之前准备的，基本上是以未经编辑的形式提供的。虽然审查员有机会根据小组的讨论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别批评意见。因此，这些评论可能不能完全反映评审员在小组讨论结束时的最终意见或小组的最终多数意见。因此，讨论纪要和总结是审查员在会议上实际上认为至关重要的最后结论。

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.