Mi: Modulating Osteoclast Gene Expression and Function

描述（由申请人提供）：小眼症转录因子（MITF）是发育无关细胞类型（包括破骨细胞和黑素细胞）的终端分化所必需的。MITF通过调节不同细胞类型中不同的靶基因集来实现这一点。我们正试图确定MITF调节破骨细胞靶基因能力的分子机制。我们最近的研究提供了两种机制，至少可以部分解释MITF选择性调节破骨细胞靶基因的能力。首先，MITF与ets家族因子PU.1的相互作用是调控靶基因和分化全功能破骨细胞所必需的。其次，MITF是nf - κ b配体受体激活因子（RANKL）通过p38丝裂原激活蛋白激酶（MAPK）信号通路的直接靶点。我们的总体假设是，MITF的修饰，通过其与PU.1的相互作用和RANKL/p38 MAPK的磷酸化，导致能够指导破骨细胞特异性基因表达程序的独特蛋白质复合物的组装。该提议有两个具体目标：目标1。探讨MITF和PU.1在破骨细胞靶基因激活和分化中的协同作用机制；目标2。确定p38丝裂原活化蛋白激酶途径增加破骨细胞MITF活性的机制。了解MITF在破骨细胞中的作用机制将提供对破骨细胞基因表达和分化的基本理解，并可能提供新的分子靶点，用于解除人类疾病中的破骨细胞，至少部分原因是这种细胞类型的过度活跃。

DESCRIPTION (provided by applicant): The microphthalmia transcription factor (MITF) is required for terminal differentiation of developmentally unrelated cell types including osteoclasts and melanocytes. MITF accomplishes this by regulating distinct sets of target genes in distinct cell types. We are trying to define the molecular mechanisms that account for the ability of MITF to regulate target genes in osteoclasts. Our recent studies provide two mechanisms that can at least partially account for the ability of MITF to selectively regulate target genes in osteoclasts. First, MITF interaction with the Ets-family factor PU.1 is required for regulation of target genes and for differentiation of fully functional osteoclasts. Second, MITF is a direct target for Receptor Activator of NF-kappaB Ligand (RANKL) action through a p38 Mitogen Activated Protein Kinase (MAPK) signaling pathway. Our overall hypothesis is that modification of MITF, through both its' interaction with PU.1 and through phosphorylation by the RANKL/p38 MAPK, leads to assembly of a unique complex of proteins capable of directing an osteoclast-specific gene expression program. The proposal has two specific aims: Aim 1. To determine the mechanism that underlies MITF and PU.1 co-operation in osteoclast target gene activation and differentiation; Aim 2. To determine the mechanism by which the p38 Mitogen Activated Protein Kinase pathway increases MITF activity in osteoclasts. Understanding the mechanism of MITF action in osteoclasts will provide a basic understanding of osteoclast gene expression and differentiation, and may also provide new molecular targets that can be used to disarm the osteoclast in human diseases that result at least in part from the hyperactivity of this cell type.