Role of VentX in macrophage differentiation and mucosal defense

描述（由申请方提供）：胃肠道粘膜的慢性炎症性损伤是炎症性肠病（IBD）的标志。IBD通常被称为克罗恩病（CD）和溃疡性结肠炎（UC），会导致相当大的慢性发病率，包括恶性肿瘤风险增加。巨噬细胞的异常激活与IBD的发病机制有关。然而，单核细胞向巨噬细胞分化和活化的转录控制仍然知之甚少。这些知识对于改善IBD的管理至关重要，IBD影响着美国100多万人。我们研究的长期目标是了解生理和病理条件下单核细胞/巨噬细胞发育的机制。该提案的目的是了解VentX如何调节巨噬细胞终末分化和激活，以及如何利用这种机制来管理IBD。VentX是一种最近受到重视的造血同源框转录因子，其表达在单核细胞至巨噬细胞终末分化期间上调。这些研究的基础是我们的中心假设：VentX是健康和疾病中巨噬细胞终末分化和激活的关键调节剂。我们的假设来自于我们最近的研究结果，该研究表明VentX促进巨噬细胞终末分化和活化，并且是巨噬细胞终末分化和活化所必需的。拟议研究的基本原理是，拟议研究的结果将为巨噬细胞终末分化和活化提供新的机制见解，这对炎症性肠病的管理至关重要。使用组合的生物信息学、生物化学和分子方法，目标1中提出的实验将集中于单核细胞-巨噬细胞终末分化期间VentX上调的机制;目标2将定义VentX控制的单核细胞-巨噬细胞终末分化的分子机制;目标3将定义VentX调节的肠粘膜巨噬细胞的促炎激活的分子机制;目标4将定义VentX调节的肠粘膜巨噬细胞的促炎激活的分子机制。目的4将探讨VentX在IBD临床管理中的作用。在我们确定VentX是巨噬细胞末端分化和激活的关键调节因子的基础上，我们处于独特的地位，可以联合收割机结合基础和临床研究的力量来定义VentX调节巨噬细胞分化和激活的机制及其在炎症性肠病管理中的潜在应用。

DESCRIPTION (provided by applicant): Chronic inflammatory damage of gastrointestinal mucosa is a hallmark of inflammatory bowel disease (IBD). Commonly known as Crohn's Disease (CD) and Ulcerative Colitis (UC), IBD causes considerable chronic morbidity, including increased risk of malignancies. Aberrant activation of macrophages has been implicated in the pathogenesis of IBD. Nevertheless, the transcriptional control of monocytes to macrophages differentiation and activation remains poorly understood. Such knowledge is crucial for improving management of IBD, which affects more than one million people in the USA. The long-term goal of our study is to understand the mechanisms of monocyte/macrophage development in physiological and pathological conditions. The objective of this proposal is to understand how macrophage terminal differentiation and activation are regulated by VentX and how this mechanism could be utilized to manage IBD. VentX is a recently appreciated hematopoietic homeobox transcriptional factor, whose expression is up-regulated during monocyte-to-macrophage terminal differentiation. Underlying the proposed studies is our central hypothesis: that VentX is a critical regulator of macrophage terminal differentiation and activation in health and disease. Our hypothesis derives from the results of our recent investigation, which showed that VentX promotes and is required for macrophage terminal differentiation and activation. The rationale for the proposed research is that the results of the proposed studies will provide novel mechanistic insight into macrophage terminal differentiation and activation, which is critical for the management of inflammatory bowel diseases. Using combined bioinformatics, biochemical and molecular approaches, the experiments proposed in Aim 1 will focus on the mechanisms of VentX up-regulation during monocyte- to-macrophage terminal differentiation; Aim 2 will define the molecular mechanisms of VentX-controlled monocyte-to-macrophage terminal differentiation; Aim 3 will define the molecular mechanisms underlying VentX-regulated pro-inflammatory activation of intestinal mucosa macrophage; and Aim 4 will explore the role of VentX in clinical management of IBD. On the basis of our identification of VentX as a key regulator of macrophage terminal differentiation and activation, we are uniquely positioned to combine the power of basic and clinical investigations to define the mechanisms of VentX-regulated macrophage differentiation and activation and their potential application in IBD management.