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Pathogenesis of inherited neuropathies: implication of components of the innate and adaptive immune system

遗传性神经病的发病机制：先天性和适应性免疫系统组成部分的影响

基本信息

批准号：
227548520
负责人：
Professor Dr. Rudolf Martini
金额：
--
依托单位：
Neurologische Klinik und Poliklinik
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/227548520?language=en
关键词：
Pathogenesis inherited neuropathies implication components

项目摘要

Charcot-Marie-Tooth (CMT) type 1 disorders are genetically-mediated neuropathies that are characterized by length-dependent axonal degeneration, muscle atrophy and sensory dysfunction, substantially reducing quality of life. Although more than 80 culprit genes have been identified so far, none of the disorders is treatable. During the last couple of years, our group has shown that in established animal models of CMT, low-grade inflammation driven by CSF-1-activated macrophages substantially amplifies the primarily genetically-mediated disorders and is, thus, a possible access point for therapeutic approaches.During the last funding period, we could unequivocally identify systemic antibodies binding to the diseased nerve fibers of P0het mutants, an established model for CMT1B, as mild modulators of macrophage function in the demyelinating process. This was achieved by an approach ablating the antibody-producing cells genetically, followed by a reconstitution of distinct antibody fractions. Two observations lead to the conclusion that the impact of the antibodies is comparably minor: i) the antibodies are not only mildly, but also transiently involved, i.e., at younger stages, only; ii) in another established model, the antibodies had no detectectable effect on pathogenesis, although decorating diseased nerve fibers. For a continuation of the project, we modified our plans aiming to identify putative major players in the tripartite interaction between mutant Schwann cells, endoneurial fibroblast and pathogenic macrophages. Based on our comprehensive pilot studies, we want in a first approach (Objective 1) to investigate whether the Schwann cell-derived growth factors PDGF-A or -B initiate CSF-1 expression in fibroblasts that activates pathogenic macrophages. For this purpose, we will use cell culture systems and an in vivo treatment approach interfering with PDGF-R. Eventually, sophisticated, timely inducible and cell specific gene knock-out experiments in vivo are planned to identify the responsible PDGF isoforms. Additionally, possible macrophage-derived factors that mediate pathogenic Schwann cell dedifferentiation are of major interest (Objective 2). As candidates for macrophage-driven Schwann cell dedifferentiation, we consider the cytokines TNF-alpha and TGF-beta. By a combination of bone-marrow transfer from cytokine-deficient mutants into myelin mutants experimentally deprived of intrinsic macrophages, we aim to analyse the impact of the cytokine-deficient macrophages on pathogenic Schwann cell dedifferentiation. All in all, our project wants to decipher the major molecular players leading to pathogenic inflammation in CMT mutants, with the aim to develop corresponding treatment strategies.

腓骨肌萎缩症 (CMT) 1 型疾病是遗传介导的神经病，其特征是长度依赖性轴突变性、肌肉萎缩和感觉功能障碍，严重降低生活质量。尽管迄今为止已经确定了 80 多个罪魁祸首基因，但没有一种疾病是可以治疗的。在过去的几年中，我们的小组已经表明，在已建立的 CMT 动物模型中，由 CSF-1 激活的巨噬细胞驱动的低度炎症大大放大了主要遗传介导的疾病，因此是治疗方法的一个可能的切入点。在最后的资助期间，我们可以明确地识别与 P0het 患病神经纤维结合的全身抗体突变体是 CMT1B 的既定模型，作为脱髓鞘过程中巨噬细胞功能的温和调节剂。这是通过一种从基因上消除抗体产生细胞，然后重建不同抗体组分的方法来实现的。两项观察结果得出这样的结论：抗体的影响相对较小：i) 抗体不仅是轻微的，而且是短暂的，即仅在较年轻的阶段； ii）在另一个已建立的模型中，尽管抗体装饰了患病的神经纤维，但对发病机制没有可检测到的影响。为了继续该项目，我们修改了计划，旨在确定突变雪旺细胞、神经内膜成纤维细胞和致病性巨噬细胞之间三方相互作用中假定的主要参与者。基于我们全面的试点研究，我们希望采用第一种方法（目标 1）来研究雪旺细胞衍生的生长因子 PDGF-A 或 -B 是否启动成纤维细胞中的 CSF-1 表达，从而激活致病性巨噬细胞。为此，我们将使用细胞培养系统和干扰 PDGF-R 的体内治疗方法。最终，计划在体内进行复杂、及时的诱导和细胞特异性基因敲除实验，以确定负责的 PDGF 亚型。此外，介导致病性雪旺细胞去分化的可能的巨噬细胞衍生因子也引起了人们的主要兴趣（目标 2）。作为巨噬细胞驱动的雪旺细胞去分化的候选者，我们考虑细胞因子 TNF-α 和 TGF-β。通过将细胞因子缺陷型突变体的骨髓转移到实验上缺乏内在巨噬细胞的髓磷脂突变体中，我们的目的是分析细胞因子缺陷型巨噬细胞对致病性雪旺细胞去分化的影响。总而言之，我们的项目希望破译导致CMT突变体致病性炎症的主要分子因素，从而制定相应的治疗策略。