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)降低了患者的生活质量，并且IBD的发病率在全球范围内呈上升趋势。此外，IBD与心脏病和中风并存，这两种疾病是导致死亡的两大原因。IBD与流向肠道的血液减少有关，而肠系膜阻力(MAS)动脉在控制流向肠道微循环的血液中所起的整体作用却鲜为人知。血管周围感觉神经(PSN)通过释放降钙素基因相关肽(CGRP)和P物质(SP)在调节血管运动功能中发挥重要作用。这些多肽与其相应的平滑肌细胞(SMCs)和内皮细胞(ECs)上的受体结合，启动细胞间和细胞内信号转导，这对维持动脉血流和组织灌流至关重要。PVSNs在影响MA扩张方面尤为重要。虽然CGRP是抗炎的，可以预防IBD，但SP是促炎的，可能会加剧疾病。值得注意的是，关于PVSNs如何受到IBD的影响和/或促进IBD的作用，人们知之甚少。因此，本项目的目标是根据PVSN在MA上的作用来确定与IBD相关的结构和功能变化。重点是明确CGRP和SP对主动脉内皮细胞和平滑肌细胞的作用，从而确定IBD时阻力动脉的中膜和内膜是如何受到影响的。我将验证中心假设，即在IBD期间，MAS的SMC和ECS中感觉神经递质功能、释放和下游信号的改变会导致流向肠道的血流受损。[为了研究这些关系，我将使用自发的慢性IBD小鼠模型(SAMP1/YitFc)，并应用药理学、免疫学和分子方法来研究回肠末端的mAs，关键实验在IL-10基因敲除的IBD小鼠模型中重复。]为了确定在IBD期间PSN介导的信号如何在动脉壁内受到影响，将通过手术分离完整的MA以进行体外研究，并将MA拱门 在体内血流控制过程中进行了研究。目的1根据CGRP和SP及其受体在SMC和ECs上的表达、分布和功能平衡，阐明IBD对PSN密度的影响。目的2将确定PSNS如何通过释放CGRP和SP来控制血管运动功能(即血管直径的变化)，它们对SMC和ECs的作用，以及IBD如何影响这些作用，特别是在内皮功能障碍的情况下。目的3将根据IBD过程中血管扩张、一氧化氮产生和白细胞黏附的情况，确定CGRP和SP诱导的内皮细胞和平滑肌细胞钙信号的性质。该项目将独一无二地确定PSN及其相关信号通路在介导血管舒缩功能和血流控制中的作用，并将确定这些通路在IBD发病机制中的影响。研究结果将为开发治疗血管功能障碍和肠道血流受损的新的选择性治疗策略提供新的见解，以提高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.