Coordination Funds

慢性瘙痒是世界范围内患者痛苦和生活质量下降的一种非常普遍的原因，但我们对其基本神经生理学和临床相关病理机制的了解有限，目前的治疗方案也是如此。另一方面，对小鼠神经性瘙痒通路的分子、细胞甚至功能描述将我们对该物种瘙痒的了解提高到了一个更高的水平。我们的研究单位PRUSEARCH开始使用来自啮齿动物的这一突破性新信息来揭示炎症性、神经性和全身瘙痒患者的临床相关瘙痒机制。我们以患者为中心，利用基础科学方法，建立了一个多学科协作网络。人类瘙痒和伤害性感觉神经元及其相关模型的神经生理学特征解决了翻译挑战，并优化了临床使用的电刺激范例。基于全面的临床表型，我们正在以标准化的方式表征不同疾病实体中的结构-功能关系，将患者报告的结果与C-纤维特定功能测试的反应性、皮肤表达模式、表皮神经纤维的创新结构参数和中枢激活模式联系起来。在保持我们研究单位第一个资助期的非常成功的基本概念的同时，我们决定特别在结构/功能关系研究方面取得进展，并加强我们对特异性和因果关系的研究方法。关键的新元素是包括局部外部因素(微生物组)，非髓鞘雪旺细胞的特征，以及在相关模型中产生功能性分子定义的瘙痒感受器。纵向观察将用于测试我们的功能和结构标记的外部有效性。因此，我们从第一个资助期提炼了我们的主要目标)确定慢性瘙痒患者炎性和非炎症性瘙痒的关键介质系统，并验证它们的外部有效性b)确定神经元和非神经细胞之间的结构/功能关系，这些关系决定慢性瘙痒的瘙痒强度)确定炎症、神经病理性和全身性瘙痒之间以及慢性神经病理性瘙痒和疼痛之间神经元敏化的共同和可能的不同机制。因此，我们的综合方法旨在澄清慢性瘙痒和疼痛状况之间目前尚不清楚的重叠之处，并旨在达成统一的诊断和治疗理解和程序。作为我们研究单位的最终目标，我们希望揭示瘙痒的临床相关病理机制，并开发一种全面的、基于机制的诊断方法，以识别炎症性、神经性和系统性瘙痒的临床相关亚型，并允许优化特定的治疗。

Chronic pruritus is a highly prevalent cause of suffering and reduced quality of life in patients worldwide, yet our understanding of its basic neurophysiology and of clinically relevant pathomechanisms is limited as are current treatment options. On the other hand, molecular, cellular and even functional characterization of neuronal itch pathways in mice have lifted our understanding of pruritus in this species to a higher level. Our research unit PRUSEARCH set out using this groundbreaking new information from rodents to uncover clinically relevant itch mechanism in patients with inflammatory, neuropathic, and systemic itch. We have established a collaborative multidisciplinary network using basic science methods in a patient-centred approach. Neurophysiologic characterization of pruriceptive and nociceptive sensory neurons in humans and relevant models addresses the translational challenge and optimizes electrical stimulation paradigms for clinical use. Based on comprehensive clinical phenotyping we are characterizing structure-function relations in the different disease entities linking patient reported outcomes to responsiveness to C-fiber specific functional tests, skin expression patterns, innovative structural parameters of epidermal nerve fibers, and central activation patterns in a standardized fashion.While keeping the highly successful basic concept of the first funding period of our research unit, we have decided to advance particularly in our attempt to investigate structure/function relations and strengthen our approaches towards specificity and causality. Key new elements are the inclusion of local external factors (microbiome), characterization of non-myelinating Schwann cells, and generation of functionalized molecularly defined pruriceptors in relevant models. Longitudinal observations will be used to test for the external validity of our functional and structural markers. Thus, we have refined our key objectives from the first funding perioda) Identify crucial mediator systems for inflammatory and non-inflammatory pruritus in chronic itch patients and validate their external validityb) Identify structure/function relations between neuronal and non-neuronal cells that determine itch intensity in chronic pruritusc) Identify common and possibly disparate mechanisms of neuronal sensitization between inflammatory, neuropathic, and systemic itch, but also between in chronic neuropathic itch and pain Thus, our comprehensive approach is intended to clarify the currently unclear overlap between chronic itch and pain conditions and aims for a harmonized diagnostic and therapeutical understanding and procedure. As ultimate objective of our research unit, we expect to uncover clinically relevant pathomechanisms in itch and to develop a comprehensive and mechanism-based diagnostic approach that identifies clinically relevant subgroups of inflammatory, neuropathic, and systemic itch and allows optimization of the specific treatment.