Movo in embryonic development and skin differentiation

描述（由申请人提供）： 作为一个独立的研究者，我有兴趣了解控制细胞分化的分子机制。哺乳动物皮肤的自我更新是研究这一过程的理想模型。我的研究团队位于加州大学欧文分校生物化学系，专注于小鼠卵细胞基因家族，这是表皮和毛囊分化所必需的。我的研究计划的长期目标是利用这些小鼠卵（movo）基因作为一个有用的分子把手，研究增殖细胞如何分化成皮肤中高度专业化的终末细胞，这些细胞在保护、感觉、温度调节和社会互动中发挥重要作用。 在接下来的5年里，我提出了两个具体的目标：1）描述MOVO基因的生物学功能。我们将描述常规movo 2基因敲除小鼠的胚胎致死表型，该小鼠的产生得到了我的R 01基金的支持。我们将专门测试的假设，movo 2是一个低流的Wnt/β-连环蛋白/LEF信号通路在胚胎发育过程中的目标。我们将通过皮肤特异性movo 2基因敲除小鼠的产生和分析来表征movo 2在表皮和毛囊分化中的功能。最后，我们将通过产生和分析双突变体来测试movo 1和movo 2之间的假定功能“冗余/补偿”。2)描述MOVO基因的分子和细胞功能。我们将研究MOVO基因在调节基因表达和细胞分化中的作用。我们将专门测试这样的假设，即mOvol 3蛋白通过与Myb转录激活因子竞争结合来抑制增殖控制基因如c-Myc和Id 2，从而使表皮和毛囊细胞沿着终末分化3途径分流。我们还将描述mOvo的转录抑制活性，并研究相互作用的蛋白质，以了解mOvo蛋白调节转录的机制。最后，我们将研究Nhether mOvo蛋白参与，直接或间接，在肌动蛋白cytotoxin驱动的过程。 这项研究将利用我在生物化学，分子生物学和小鼠发育遗传学方面的现有专业知识。它还将使我获得分子胚胎学和生物信息学领域的新技能。K 02奖将极大地促进我作为研究科学家的持续发展，并帮助我实现使用多学科方法解决重要生物学问题的目标。

DESCRIPTION (provided by applicant): As an independent investigator, I am interested in understanding the molecular mechanisms controlling cellular differentiation. The self-renewing mammalian skin is an excellent model system to study this process. My research team, situated in the Department of Biological Chemistry at the University of California-lrvine, focuses on the mouse ovo family of genes, which are required for the differentiation of the epidermis and hair follicles. The long-term goal of my research program is to use these mouse ovo (movo) genes as a useful molecular handle to study how proliferative cells differentiate into highly specialized terminal cells in the skin that play important roles in protection, sensation, temperature regulation, and social interaction. For the next 5-year period, I propose two specific aims: 1) Characterize the biological functions ofmovo genes. We will characterize the embryonic lethal phenotype of conventional movo2 knockout mice, the generation of which was supported by my R01 grant. We will specifically test the hypothesis that movo2 is a -lownstream target of the Wnt/beta-catenin/LEF signaling pathway during embryonic development. We will characterize the function of movo2 in epidermal and hair follicle differentiation through the generation and analysis of skin-specific movo2 knockout mice. Finally, we will test the putative functional "redundancy/compensation between movo1 and movo2 by generating and analyzing double mutants. 2) characterize the molecular and cellular functions of movo genes. We will investigate the role of movo genes in "egulating gene expression and cellular differentiation. We will specifically test the hypothesis that mOvol 3rotein represses proliferation control genes such as c-Myc and Id2 by competing for binding with the Myb transcriptional activators, thereby shunting the epidermal and hair follicle cells down a terminal differentiation 3athway. We will also characterize the transcription repressor activity of mOvo and study interacting proteins n order to understand the mechanism by which mOvo proteins regulate transcription. Finally, we will examine Nhether mOvo proteins are involved, directly or indirectly, in actin cytoskeleton-driven processes. This research will utilize my existing expertise in biochemistry, molecular biology, and mouse developmental genetics. It will also allow me to acquire new skills in the areas of molecular embryology and bioinformatics. A K02 award will greatly facilitate my continued development as a research scientist, and help me to achieve my goal of using a multi-disciplinary approach to address important biological questions.