Interaction of Mesenteric Adipose Tissue Physiology, Expansion, and Inflammation with Inflammatory Bowel Disease

项目摘要 在过去的二十年里，炎症性肠病的患病率急剧增加。 (IBD)，如溃疡性结肠炎和克罗恩病，与肥胖流行不谋而合。肥胖与脂肪 组织炎症与全身代谢紊乱有关，因为其他器官应对有毒水平的 脂类，否则将安全地储存在脂肪细胞中。另外重要的是，脂肪组织是一种活跃的 分泌大量脂肪因子的内分泌器官，包括激素和细胞因子，调节全身 葡萄糖动态平衡、脂肪代谢、炎症等许多生理过程。多个临床 动物研究表明，腹内脂肪或内脏脂肪的膨胀与 IBD负担加重。肠系膜内脏脂肪组织储存库(MAT)包围和支撑 胃肠道，在肥胖期间急剧扩张，并与不利的治疗相关 IBD的转归。然而，研究肠系膜脂肪组织是具有挑战性的，因为它是一种高度淋巴和 细胞异质组织。在这项提议中，我应用了分离成熟脂肪细胞的方法， 脂肪细胞前体细胞和免疫细胞，这样我就可以研究垫在 肥胖症和垫炎症如何影响IBD的进展。 文献和我们的初步数据表明，在肥胖期间，垫的扩张和重塑是 与其他内脏脂肪库不同。因此，我假设在肥胖期间，MAT会经历 适应不良的重塑，引发炎性级联反应，加重小鼠的IBD。第一个目标是 用脂肪细胞和脂肪细胞祖细胞谱系追踪确定肥胖过程中的病理性垫扩张 小鼠模型，免疫系统的深入特征，以及单细胞RNA测序方法。这个 第二个目的将确定垫炎症在IBD进展中的重要性。胃肠道 可以理解的是，一直是几个成熟的小鼠模型的主要研究重点，这些模型与 类似于人类克罗恩氏病。我的总体方法将集中在垫子生物学和作用 肠交界处的肠系膜脂肪细胞炎症。为了研究IBD期间的垫子/肠道串扰，我将 用小鼠模型以诱导的方式改变垫上的炎症并观察其对严重程度的影响 肠道损伤和炎症。 目前，IBD的治疗需求尚未得到满足，也没有针对IBD的MAT靶向治疗。 因此，了解肥胖期间肠系膜脂肪组织及其与 肠道可能为IBD的新生物标志物和治疗策略开辟一个富有成效的研究领域。

Project Summary Over the past two decades there has been a dramatic increase in the prevalence of inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease, coincident with the obesity epidemic. Obesity and adipose tissue inflammation are linked to whole-body metabolic disturbances as other organs cope with toxic levels of lipid, which would otherwise be safely stored in adipocytes. Of additional importance, adipose tissue is an active endocrine organ that secretes numerous adipokines including hormones and cytokines, regulating systemic glucose homeostasis, lipid metabolism, inflammation, and many other physiological processes. Many clinical and animal studies show a strong link between expansion of intra-abdominal fat, or visceral fat, and increased burden of IBD. The mesenteric visceral adipose tissue depot (MAT) surrounds and supports the gastrointestinal tract, dramatically expands during obesity, and is associated with unfavorable therapeutic outcomes for IBD. However, studying mesenteric adipose tissue is challenging as it is a highly lymphatic and cellularly heterogenous tissue. In this proposal I have applied methods that will isolate mature adipocytes, adipocyte progenitors, and immune cells so that I can study the unique way MAT remodels during obesity and how MAT inflammation affects the progression of IBD. The literature and our preliminary data suggest that during obesity MAT expansion and remodeling is different than other visceral adipose depots. Therefore, I hypothesize that during obesity, MAT undergoes maladaptive remodeling, initiating inflammatory cascades that exacerbates IBD in mice. The first Aim will define pathological MAT expansion during obesity using adipocyte and adipocyte progenitor lineage-tracing mouse models, in-depth characterization of the immune system, and single-cell RNA-sequencing methods. The second Aim will determine the importance of MAT inflammation to IBD progression. The gastrointestinal tract has understandably been the primary focus of study for several well-established mouse models that closely resemble human Crohn's disease. My general approach will be to focus on MAT biology and the role of mesenteric adipocyte inflammation at the intestinal interface. To study MAT/intestinal crosstalk during IBD, I will use mouse models to alter inflammation in MAT in an inducible manner and observe the effect on the severity of intestinal damage and inflammation. Currently, there is an unmet need for the treatment of IBD and no MAT-targeted treatments for IBD exist. Therefore, an understanding of mesenteric adipose tissue during obesity and its communication to the intestine may open up a fruitful area of research for new biomarkers and therapeutic strategies for IBD.