Ionic Mechanisms of Stretch-Activation in Muscular Lymphatics

描述（由申请人提供）：为了实现淋巴系统在体液调节、大分子稳态、脂质吸收、免疫功能中的作用，它必须将淋巴液从淋巴结运输，沿着淋巴网络，通过淋巴结，进入颈部大静脉。淋巴肌利用紧张性和阶段性收缩以及肌肉收缩蛋白的独特组合来产生和控制淋巴流动/运输。淋巴肌的收缩受物理和离子事件的驱动和调节。淋巴管壁的伸展是淋巴功能的最有据可查的物理刺激物。淋巴肌离子事件驱动电活动和细胞内钙以调节收缩。然而，调节淋巴肌收缩的离子机制以及拉伸如何激活它们相对未知。为了更好地了解淋巴功能的调节，我们建议研究淋巴肌收缩的离子机制以及它们如何受到牵拉的影响。功能障碍性神经系统疾病导致广泛的临床问题。该项目将大大推进我们对淋巴生物学的理解，并为诊断和治疗淋巴收缩功能障碍的治疗策略的最终发展提供基础。公共卫生相关性：为了实现淋巴系统在体液和大分子调节、脂质吸收和免疫功能中所起的作用，它利用淋巴肌的收缩来产生和控制淋巴流量，将淋巴液从淋巴结沿着淋巴网络通过淋巴结输送到颈部的大静脉中。然而，调节淋巴肌收缩的离子机制以及拉伸（调节淋巴泵的主要物理因素）如何激活它们尚不清楚。该项目将大大推进我们对淋巴生物学的理解，并为治疗淋巴收缩功能障碍的治疗策略的发展提供基础，淋巴收缩功能障碍可能导致广泛的临床问题。

DESCRIPTION (provided by applicant): To fulfill the roles the lymphatic system plays in body fluid regulation, macromolecular homeostasis, lipid absorption, immune function, it must transport lymph from the interstitium, along the lymphatic network, through the nodes, into the great veins of the neck. Lymphatic muscle utilizes a unique combination of tonic and phasic contractions and muscle contractile proteins to generate and control lymph flow/transport. Contraction of lymphatic muscle is driven and regulated by both physical and ionic events. Stretch of the lymphatic wall is the most well documented physical stimulator of lymphatic function. Lymphatic muscle ionic events drive the electrical activity and intracellular calcium to modulate contraction. However, the ionic mechanisms regulating lymphatic muscle contraction and how stretch activates them are relatively unknown. To gain a better understanding of the regulation of lymphatic function, we propose to investigate the ionic mechanisms of lymphatic muscle contraction and how they are affected by stretch in isolated rat mesenteric lymphatics. Dysfunctional lymphatics result in a wide range of clinical problems. This project will substantially advance our understanding of lymphatic biology and provide the basis for the eventual development of therapeutic strategies to diagnose and treat lymphatic contractile dysfunction. PUBLIC HEALTH RELEVANCE: To fulfill the roles the lymphatic system plays in body fluid and macromolecular regulation, lipid absorption and immune function, it transports lymph from the interstitium, along the lymphatic network, through the nodes, into the great veins of the neck using contractions of the lymphatic muscle to generate and control lymph flow. However, the ionic mechanisms regulating lymphatic muscle contraction and how stretch (the predominant physical factor that regulate lymph pumping) activates them are unknown. This project will substantially advance our understanding of lymphatic biology and provide the basis for the development of therapeutic strategies to treat lymphatic contractile dysfunction, which can result in a wide range of clinical problems.