Role of VentX in macrophage differentiation and mucosal defense

描述（由申请人提供）：胃肠道黏膜慢性炎症损伤是炎症性肠病（IBD）的标志。通常被称为克罗恩病（CD）和溃疡性结肠炎（UC）， IBD引起相当大的慢性发病率，包括恶性肿瘤的风险增加。巨噬细胞的异常活化与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影响着美国超过100万人。我们研究的长期目标是了解单核细胞/巨噬细胞在生理和病理条件下的发育机制。本提案的目的是了解巨噬细胞末端分化和激活是如何被VentX调节的，以及如何利用这一机制来管理IBD。VentX是最近发现的一种造血同源盒转录因子，其表达在单核细胞向巨噬细胞终末分化过程中上调。这些研究的基础是我们的中心假设：在健康和疾病中，VentX是巨噬细胞末端分化和激活的关键调节因子。我们的假设来源于我们最近的研究结果，该研究表明VentX促进巨噬细胞末端分化和激活，并且是必需的。提出这项研究的基本原理是，提出的研究结果将为巨噬细胞末端分化和激活提供新的机制见解，这对炎症性肠病的治疗至关重要。结合生物信息学、生化和分子方法，Aim 1的实验将重点研究单核细胞向巨噬细胞终末分化过程中VentX上调的机制；目的2将定义ventx控制的单核细胞向巨噬细胞终端分化的分子机制；目的3将明确ventx调控肠黏膜巨噬细胞促炎激活的分子机制；Aim 4将探讨VentX在IBD临床治疗中的作用。在我们确定VentX是巨噬细胞末端分化和激活的关键调节剂的基础上，我们具有独特的优势，可以结合基础和临床研究的力量来确定VentX调节的巨噬细胞分化和激活的机制及其在IBD治疗中的潜在应用。

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.