Role of perivascular nerves and vascular dysfunction in inflammatory bowel disease

 描述（由申请人提供）：项目摘要/摘要炎症性肠病（IBD）降低了受影响者的生活质量，并且IBD的发病率在全球范围内不断增加。此外，IBD与心脏病和中风共病，这是两种主要的死亡原因。IBD与肠道血流量减少有关，肠系膜阻力（MA）动脉控制血液流入肠道微循环的作用不可或缺，但研究不足。血管周围感觉神经（PSNs）通过释放降钙素基因相关肽（CGRP）和P物质（SP）在血管功能调节中起重要作用。这些多肽与平滑肌细胞（SMC）和内皮细胞（EC）上的相应受体结合，以启动对维持动脉血流和组织灌注至关重要的细胞间和细胞内信号传导。PVSN在实现MA扩张中特别重要。虽然CGRP具有抗炎作用，可以预防IBD，但SP具有促炎作用，可能会加剧疾病。值得注意的是，很少有人知道PVSN如何受到IBD的影响和/或导致IBD。因此，本项目的目标是根据PVSN对MA的作用，定义PVSN中IBD相关的结构和功能变化。重点是确定CGRP和SP对MA的SMC和EC的作用，从而确定IBD中阻力动脉的中膜和内膜如何受到影响。我将测试的中心假设，改变感觉神经递质的功能，释放和下游信号的SMC和EC的MA导致受损的血流量在IBD肠。[To为了研究这些关系，我将使用慢性IBD的自发小鼠模型（SAMP 1/YitFc），并应用药理学，免疫学和分子方法研究末端回肠的MA，并在IBD的白细胞介素10（IL-10）敲除小鼠模型中重复关键实验。为了确定在IBD期间PSN介导的信号传导如何在动脉壁内受到影响，将通过手术分离完整的MA用于体外研究，并且将在动脉壁内形成MA弓。 在体内血流控制过程中进行研究。目的1从CGRP和SP及其受体在平滑肌细胞和内皮细胞上的表达、分布和功能平衡的角度，探讨IBD对PSNs密度的影响。目的2将确定PSN如何控制血管功能（即，血管直径的变化），它们对SMC和EC的作用以及这些作用如何受到IBD的影响，特别是鉴于内皮功能障碍。目的3探讨CGRP和SP在炎症性肠病血管舒张、一氧化氮生成和白细胞粘附过程中对内皮细胞和平滑肌细胞钙信号转导的影响。该项目将独特地定义PSN及其相关信号通路在介导血管功能和血流控制中的作用，并将确定这些通路在IBD发病过程中如何受到影响。研究结果将为开发新的和选择性的治疗策略提供新的见解，用于治疗血管功能障碍和肠血流受损，以改善IBD患者的生活质量。

 DESCRIPTION (provided by applicant): Project Summary/Abstract Inflammatory bowel disease (IBD) decreases quality of life of those affected, and the incidence of IBD is increasing worldwide. Further, IBD is comorbid with heart disease and stroke, the two leading causes of death. IBD is associated with decreased blood flow to the intestines, with an integral yet poorly-studied role for the mesenteric resistance (MAs) arteries that control blood flow into the intestinal microcirculation. Perivascular sensory nerves (PSNs) play a critical role in regulation of vasomotor function through release of calcitonin gene-related peptide (CGRP) and substance P (SP). These polypeptides binds to their respective receptors on smooth muscle cells (SMCs) and endothelial cells (ECs) to initiate inter- and intracellular signaling that is critical to maintaining arterial blood flow and tissue perfusion. PVSNs are particularly important in effecting MA dilation. While CGRP is anti-inflammatory and may protect against IBD, SP is proinflammatory and may exacerbate the disease. Remarkably, little is known of how PVSNs are affected by and/or contribute to IBD. Therefore, the goal of this project is to define IBD-related structural and functional changes in PVSNs in light of their actions on MAs. A key emphasis is to define the actions of CGRP and SP on SMCs and ECs of MAs and thereby determine how the media and intima of resistance arteries are affected in IBD. I will test the central hypothesis that altered sensory neurotransmitter function, release and downstream signaling in SMCs and ECs of MAs lead to impaired blood flow to the intestine during IBD. [To investigate these relationships, I will use a spontaneous mouse model of chronic IBD (SAMP1/YitFc) and apply pharmacological, immunological and molecular approaches to study MAs of the terminal ileum, with key experiments repeated in the interleukin 10 (IL-10) knockout mouse model of IBD.] To determine how PSN-mediated signaling is affected within the arterial wall during IBD, intact MAs will be surgically isolated for in vitro studies and MA arcades will be studied during blood flow control in vivo. Aim 1 will define how the density of PSNs is affected by IBD in light of the expression, distribution and functional balance of CGRP and SP and their respective receptors on SMCs and ECs. Aim 2 will determine how PSNs control vasomotor function (i.e., changes in vessel diameter) through the release of CGRP and SP, their actions on SMCs and ECs and how these roles are affected by IBD, particularly in light of endothelial dysfunction. Aim 3 will determine the nature of calcium signaling in ECs and SMCs that are evoked by CGRP and SP in light of vasodilation, nitric oxide production and leukocyte adhesion during IBD. This project will uniquely define the role of PSNs and their associated signaling pathways in mediating vasomotor function and therefore blood flow control, and it will determine how these pathways are affected during the pathogenesis of IBD. Results will provide new insight towards developing novel and selective therapeutic strategies for treating vascular dysfunction and impaired intestinal blood flow to improve quality of life for IBD patients.