Novel regulatory mechanisms of the osteoclast transcriptional program

简介(申请人提供)：自14年前大学毕业以来，我一直致力于学术生物医学研究。上世纪90年代，作为纽约大学的一名博士生，我致力于研究对口腔病原体的先天免疫反应。2001年，我以优异的成绩从医学院毕业后，接受了内科和风湿病学的培训。两年前，我决定跟随世界著名的免疫学家和转录因子生物学家劳里·格里姆彻博士继续我职业生涯的博士后阶段。在Glimcher博士的实验室里，我对破骨细胞的骨吸收产生了浓厚的兴趣。破骨细胞的失调是肌肉骨骼疾病的发病机制之一，我在我每周的风湿病门诊中看到了这些疾病，如骨质疏松和炎症性关节炎。活化T细胞核因子(NFATs)是细胞分化途径中重要的转录因子家族，参与破骨细胞的发生。我们使用Cre-loxP技术产生了NFATd的小鼠条件基因敲除。缺失NFATd会导致骨化病和破骨细胞生成缺陷。在目标1中，在生理条件下和糖皮质激素诱导的骨质疏松模型中，探讨了NFATd在破骨细胞中的作用。我们最近发现，在缺乏NFATd的情况下，破骨细胞前体产生骨保护素，这是一种有效的破骨细胞分化抑制因子。在目标2中，对这种观察的机制和结果进行了探讨。最后，使用RNAi技术的高通量筛选已经启动，以确定新的破骨细胞分化调节因子。《目标3》试图验证在初始屏幕中确定的目标，并生成一个目标列表，以便在我职业生涯即将到来的阶段进行探索。格里姆彻博士的实验室和哈佛大学生物医学社区是追求这些雄心勃勃的项目的理想环境。骨骼生物学方面的专业知识围绕着我们，我已经建立了适当的导师和合作者。这些实验和我的职业发展计划将训练我所需的技术，以指导一个专注于阐明破骨细胞发育和病理性骨破坏机制的实验室。骨质疏松症是一种毁灭性的疾病，会导致骨骼脆弱，并困扰着数百万美国人。破骨细胞是唯一能够破坏骨骼的细胞。这项资助旨在定义调控破骨细胞发育和功能的基因。

DESCRIPTION (provided by applicant): Since graduating college 14years ago, I have committed myself to a career in academic biomedical research. As a PhD student at New York University in the 1990s, I worked on innate immune responses to oacterial pathogens. After completing medical school with high honors in 2001, I trained in both Internal Medicine and Rheumatology. Two years ago, I decided to pursue the post-doctoral phase of my career with Dr. Laurie Glimcher, a world-renowned immunologist and transcription factor biologist. In Dr. Glimcher's lab, I have developed a keen interest in bone resorption by osteoclasts. Dysregulation of osteoclasts contributes to the pathogenesis of musculoskeletal disorders that I see in my weekly rheumatology clinic, such as osteoporosis and inflammatory arthritis. Nuclear Factor of Activated T-cells (NFATs) are a family of transcription factors important for cellular differentiation pathways and have been implicated in osteoclastogenesis. We generated a murine conditional knockout of NFATd using Cre-loxP technology. Deletion of NFATd results in osteopetrosis and a defect in osteoclastogenesis. In Aim 1, the role of NFATd in osteoclasts is explored under physiologic conditions and in a model of glucocorticoid-induced osteoporosis. We have recently discovered that in the absence of NFATd, osteoclast precursors make osteoprotegerin, a potent inhibitor of osteoclast differentiation. In Aim 2, the mechanism and consequence of this observation is explored. Lastly, a high throughput screen using RNAi technology has been initiated to identify novel regulators of osteoclast differentiation. Aim 3 seeks to validate the "hits" identified in the initial screen and generate a list of targets to explore during the impendent phase of my career. Dr. Glimcher's lab and the Harvard University Biomedical community is the ideal setting to pursue these ambitious projects. Expertise in skeletal biology surrounds us and I have established the appropriate mentors and collaborators. These experiments and my career development plan will train me in the techniques needed to direct a laboratory focused on elucidating the mechanisms of osteoclast development and pathologic bone destruction. Osteoporosis is a devastating disease that causes brittle bones and afflicts millions of Americans. The osteoclast is the only cell capable of destroying bone. This grant seeks to define the genes that regulate the development and function of the osteoclast.