Notch function in postnatal intestinal and mesenteric lymphatics

项目摘要/摘要 肠道淋巴系统具有生理功能，包括摄取脂质、维生素、免疫。 监控和液体动态平衡。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 Notch在淋巴管内皮细胞命运决定和维持中的作用 肠道淋巴动态平衡。Notch信号在整个肠道淋巴系统中都很活跃， 包括导管、瓣膜和乳管淋巴管内皮。中断陷波信号或Mmp14导联 共用淋巴管源性和肠系膜淋巴瓣缺陷症。Notch和MMP14与不同的 肠道和心血管疾病以及我们的新研究将阐明它们在肠道中的作用 将淋巴缺陷作为潜在因素的疾病。我们假设Notch调节 MMPs和MMPs诱导肠和肠系膜淋巴管的细胞外基质 以一种上下文相关的方式调节基质蛋白。为了解决这一假设，我们将确定 淋巴管内皮Notch在出生后肠道和肠系膜淋巴管中的作用。我们将使用 转基因小鼠对肠和肠系膜淋巴管内皮细胞转录水平的Notch反应 细胞和系链配基实验中。Notch调控Mmp14表达的机制及其意义 对淋巴管内皮细胞行为的影响将被确定。有条件的老鼠将被用来改变 淋巴管内皮细胞Mmp14缺失和缺失对淋巴管内皮细胞Notch信号转导的影响 Notch在肠系膜淋巴集合管成熟和动态平衡中的作用。由于凹槽处于活动状态 在乳汁内皮细胞和Notch突变体表现出乳汁缺陷时，我们将使用条件性小鼠模型 研究Notch在乳汁发育和动态平衡中的作用。我们将确定是否 Antxr1-/-；Antxr2-/-小鼠绒毛中异常基质堆积导致淋巴功能障碍和 改变淋巴管内皮细胞Notch信号。我们提议的研究旨在通过以下方式揭示机制 哪个Notch调控淋巴管内皮细胞的细胞外基质蛋白和调控通路 了解消化道淋巴管的发育、动态平衡和功能。

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.