INTEGRATING CELL & LIPOPROTEIN TRAFFICKING WITH VASCULAR BIOLOGY IN HUMAN IBD

 描述（由申请人提供）：对微生物组的日益深入的了解和易感基因的鉴定改变了寻求减少炎症性肠病（IBD）健康负担的研究人员的前景。尽管取得了这些进展，并扩大了正常和患病肠道中免疫活性的细节，但与IBD病程相关的基本观察结果仍然无法解释。例如，克罗恩病的关键特征包括透壁性炎症，以发炎和患病的肠段与肠的正常区域分离为特征的“跳跃”病变，以及众所周知的“蠕动脂肪”，其中IBD强度的一个迹象是脂肪的出现不再停留在其通常的边界沿着抗-在肠壁周围逐渐蠕动，而是逐渐在肠壁上方和周围蠕动。这些特征都没有在遗传、分子或细胞水平上得到解释，但可以肯定的是，它们与克罗恩病最令人痛苦的并发症有关：纤维狭窄病变的形成是患者接受手术的主要原因，通常是紧急手术以预防肠梗阻，并且有一大群患者在疾病过程中反复经历。这项工作将为IBD的研究带来新的概念和技术方法，这些方法有可能改变我们对人类克罗恩病作为IBD主要形式的理解。总体假设是血管重塑是疾病的核心，它部分具有免疫学基础，并且其重塑与淋巴管系统的改变密切相关，淋巴管系统的改变反过来有助于疾病的发病机制和纤维化。我们将开展以患者为基础的研究来解决这一假设。

 DESCRIPTION (provided by applicant): An increasingly in-depth understanding of the microbiome and identification of susceptibility genes have changed the landscape for researchers seeking to reduce the health burden of inflammatory bowel disease (IBD). Despite these advances, and expanding detail of immunological activities in normal and diseased intestine, fundamental observations related to the course of disease in IBD remain starkly unexplained. For instance, key features of Crohn's disease include transmural inflammation, "skip" lesions characterized by the separation of inflamed and diseased intestinal segments with normal regions of intestine, and the proverbial "creeping fat" in which a tell-tale sign of the intensity of IBD is the appearance of fat that no longer stops at its usual boundary along the anti-mesenteric border but instead progressively creeps over and around the intestinal wall. None of these features are explained at a genetic, molecular, or cellular level, and yet surely they relate to the most harrowing complication of Crohn's disease: the formation of fibrostenotic lesions that serve as the principal cause for patients to be admitted to surgery, often emergency surgery to prevent bowel obstruction, and for which a large subgroup of patients experience repeatedly through the course of their disease. The work proposed will bring new approaches, conceptual and technical, to the study of IBD that have potential to transform our understanding of human Crohn's disease as a major form of IBD. The overarching hypothesis is that blood vessel remodeling is at the core of the disease, that it has in part an immunological basis, and that its remodeling goes hand-in-hand with alterations in the lymphatic vasculature that in turn contributes to disease pathogenesis and fibrosis. We will carry out patient-based studies to address this hypothesis.