Notch function in postnatal intestinal and mesenteric lymphatics

项目概要/摘要 肠淋巴系统具有生理功能，包括摄取脂质、维生素、免疫调节剂和免疫调节剂。 监视和体液平衡它由不同的淋巴管内皮细胞群组成， 需要调节途径来维持淋巴管的命运、微环境和功能。我们有 证明Notch在淋巴管内皮细胞的细胞命运决定中起作用， 肠淋巴稳态Notch信号在整个肠淋巴系统中是活跃的， 包括导管、瓣膜和乳淋巴管内皮。中断Notch信号或Mmp 14导联 共同的淋巴管生成和肠系膜淋巴瓣缺陷。Notch和MMP 14与多种 肠道和心血管疾病，我们的新研究将阐明它们在肠道疾病中的作用。 以淋巴缺陷为潜在因素的疾病。我们假设Notch调节了 肠和肠系膜淋巴管系统的细胞外基质通过诱导MMPs和 以上下文依赖的方式调节基质蛋白。为了解决这个问题，我们将确定 淋巴管内皮Notch功能在出生后肠和肠系膜淋巴管中的作用。我们将使用 肠和肠系膜淋巴管内皮细胞中转录谱Notch反应的转基因小鼠 细胞和在系链-配体测定中。Notch调控Mmp 14表达的机制及其对肿瘤生长的影响 将确定对淋巴管内皮细胞行为的影响。条件小鼠将用于改变 淋巴管内皮Notch信号传导，有和没有淋巴管内皮Mmp 14缺失，以确定 Notch在肠系膜淋巴集合管成熟和稳态中的作用。由于Notch处于活动状态， 在显示乳缺陷的乳内皮细胞和Notch突变体中，我们将使用条件小鼠模型 研究Notch在哺乳动物乳汁发育和稳态中的作用。我们将确定是否 Antxr 1-/-; Antxr 2-/-小鼠绒毛中异常基质积累导致淋巴功能障碍， 改变淋巴内皮Notch信号传导。我们提出的研究旨在揭示机制， Notch调节淋巴管内皮细胞中的细胞外基质蛋白和调节途径 了解消化道淋巴管的发育，稳态和功能。

PROJECT SUMMARY/ABSTRACT The intestinal lymphatic system serves physiological functions, including uptake of lipids, vitamins, immune surveillance, and fluid homeostasis. It is made up of distinct lymphatic endothelial cell populations that require regulatory pathways to maintain lymphatic vessel fate, microenvironment and functionality. We have demonstrated that Notch functions in cell fate determination of lymphatic endothelial cells and to maintain intestinal lymphatic homeostasis. Notch signaling is active throughout the intestinal lymphatic system, including the ductal, valve, and lacteal lymphatic endothelium. Disrupting Notch signaling or Mmp14 leads to shared lymphangiogenic and mesenteric lymphatic valve defects. Notch and MMP14 are linked to diverse intestinal and cardiovascular disorders and our novel studies will shed light on their role in intestinal diseases that have lymphatic defects as an underlying factor. We hypothesize that Notch regulates the extracellular matrix of the intestinal and mesenteric lymphatic vasculature via induction of MMPs and regulation of matrix proteins in a context-dependent manner. To address this hypothesis, we will determine lymphatic endothelial Notch function in postnatal intestinal and mesenteric lymphatics. We will use transgenic mice to transcriptional profile Notch responses in intestinal and mesenteric lymphatic endothelial cells and in a tether-ligand assay. The mechanism by which Notch regulates Mmp14 expression and its effects on lymphatic endothelial cell behavior will be determined. Conditional mice will be used to alter lymphatic endothelial Notch signaling with and without lymphatic endothelial Mmp14 deletion to define Notch functions in maturation and homeostasis of mesenteric lymphatic collecting ducts. As Notch is active in lacteal endothelial cells and Notch mutants display lacteal defects, we will use conditional mouse models to study the role of Notch in the lacteals during development and homeostasis. We will determine if abnormal matrix accumulation in the villi in Antxr1-/-;Antxr2-/- mice leads to lymphatic dysfunction and changes lymphatic endothelial Notch signaling. Our proposed research aims to uncover mechanisms by which Notch modulates extracellular matrix proteins and regulatory pathways in lymphatic endothelial cells to understand digest tract lymphatic development, homeostasis and function.