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Notch function in postnatal intestinal and mesenteric lymphatics

产后肠道和肠系膜淋巴管的 Notch 功能

基本信息

批准号：
9239036
负责人：
CARRIE J. SHAWBER
金额：
$ 41.49万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9239036
关键词：
ANTXR2 gene Address Behavior Biological Biological Assay Biology Blood Blood Vessels Cardiovascular Diseases Cells Collagen Data Defect Deposition Development Disease Duct (organ) structure Ductal Endothelial Cells Ensure Extracellular Matrix Extracellular Matrix Proteins Fibronectins Functional disorder Gastrointestinal tract structure Genes Genetic Genetic Transcription Glycocalyx Homeostasis Human Immunologic Surveillance Impairment In Vitro Inflammatory Bowel Diseases Integrin alpha1 Intestinal Diseases Intestines Knowledge Laminin Ligands Light Link Lipids Liquid substance Lymphangiogenesis Lymphatic Lymphatic Capillaries Lymphatic Endothelial Cells Lymphatic Endothelium Lymphatic System Lymphatic vessel MMP14 gene MMP2 gene Matrix Metalloproteinases Mesentery Mus Pathology Pathway interactions Pericytes Phenotype Physiological Population Proteins Regulation Regulatory Pathway Research Role Signal Transduction Smooth Muscle Myocytes Stem cells Submucosa Tissues Transgenic Mice Tumor Angiogenesis Villus Vitamins cell behavior cell growth cell motility cell type gastrointestinal system gene function in vivo integrin alpha9 migration mouse model mutant notch protein novel postnatal response uptake

项目摘要

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.

项目概要/摘要肠道淋巴系统具有生理功能，包括摄取脂质、维生素、免疫功能监测和体液稳态。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发挥作用并维持肠道淋巴稳态。 Notch 信号在整个肠道淋巴系统中都很活跃，包括导管、瓣膜和乳肠淋巴管内皮。破坏 Notch 信号或 Mmp14 引线共同的淋巴管生成和肠系膜淋巴瓣缺陷。 Notch 和 MMP14 与多种相关肠道和心血管疾病，我们的新研究将揭示它们在肠道和心血管疾病中的作用以淋巴缺陷为潜在因素的疾病。我们假设 Notch 调节通过诱导 MMP 和肠和肠系膜淋巴管系统的细胞外基质以上下文相关的方式调节基质蛋白。为了解决这个假设，我们将确定淋巴内皮Notch在产后肠道和肠系膜淋巴管中的功能。我们将使用转基因小鼠对肠和肠系膜淋巴内皮转录谱的Notch反应细胞和系链配体测定中。 Notch调控Mmp14表达的机制及其将确定对淋巴内皮细胞行为的影响。有条件的老鼠将被用来改变淋巴管内皮Notch信号传导有或没有淋巴管内皮Mmp14缺失来定义 Notch 在肠系膜淋巴管的成熟和稳态中发挥作用。当 Notch 处于活动状态时在乳汁内皮细胞和Notch突变体中表现出乳汁缺陷，我们将使用条件小鼠模型研究Notch在发育和稳态过程中乳糜管中的作用。我们将确定是否 Antxr1-/-;Antxr2-/- 小鼠绒毛中异常基质积聚导致淋巴功能障碍改变淋巴管内皮 Notch 信号传导。我们提出的研究旨在揭示机制 Notch 调节淋巴内皮细胞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。