Novel regulatory mechanisms of the osteoclast transcriptional program

破骨细胞转录程序的新调控机制

基本信息

批准号：
7806494
负责人：
ANTONIOS O ALIPRANTIS
金额：
$ 13.1万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7806494
关键词：
Adult Albers-Schonberg disease Alleles American Biology Biomedical Research Bone Resorption Cardiac Cells Clinic Commit Communities Data Defect Development Development Plans Disease Doctor of Philosophy Embryo Enzymes Family Gene Mutation Genes Glucocorticoids Grant Heart Valves Homeostasis Immune Cell Activation Immune response Immunologist In Vitro Internal Medicine Investigation Knock-out Knockout Mice Laboratories Learning Mediating Mentors Microarray Analysis Modeling Molecular Mus Muscle Development Musculoskeletal Diseases New York Osteoblasts Osteoclasts Osteogenesis Osteoporosis Pathogenesis Pathologic Pathway interactions Phase Physiological Postdoctoral Fellow Process RNA RNA Interference Repression Rheumatoid Arthritis Rheumatology Role Signaling Molecule Skeletal Muscle Skeleton Students System TNFSF11 gene Techniques Technology Tissues Training Tumor necrosis factor receptor 11b Universities Vertebrates Work base bone bone mass career career development clinically relevant college flexibility high throughput screening in utero in vivo inhibitor/antagonist interest medical schools novel nuclear factors of activated T-cells osteoclastogenesis pathogen progenitor programs research study response skeletal skeletal disorder therapeutic target transcription factor

项目摘要

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.

描述（由申请人提供）：自从 14 年前大学毕业以来，我一直致力于学术生物医学研究的职业生涯。 20 世纪 90 年代，作为纽约大学的一名博士生，我致力于研究细菌病原体的先天免疫反应。 2001 年以优异的成绩从医学院毕业后，我接受了内科和风湿病学方面的培训。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 Laurie Glimcher 博士继续我职业生涯的博士后阶段。在 Glimcher 博士的实验室中，我对破骨细胞的骨吸收产生了浓厚的兴趣。破骨细胞的失调导致了我在每周的风湿病门诊中看到的肌肉骨骼疾病的发病机制，例如骨质疏松症和炎症性关节炎。激活 T 细胞核因子 (NFAT) 是一个对细胞分化途径很重要的转录因子家族，与破骨细胞生成有关。我们使用 Cre-loxP 技术产生了 NFATd 的小鼠条件性敲除。 NFATd 缺失会导致石骨症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症模型中探讨了 NFATd 在破骨细胞中的作用。我们最近发现，在缺乏 NFATd 的情况下，破骨细胞前体会产生骨保护素，这是一种有效的破骨细胞分化抑制剂。在目标 2 中，探讨了这一观察结果的机制和结果。最后，使用 RNAi 技术的高通量筛选已启动，以确定破骨细胞分化的新型调节剂。《目标 3》旨在验证初始屏幕中确定的“目标”，并生成一个目标列表，供我职业生涯即将到来的阶段探索。 Glimcher 博士的实验室和哈佛大学生物医学界是实现这些雄心勃勃的项目的理想场所。我们拥有骨骼生物学方面的专业知识，我已经找到了合适的导师和合作者。这些实验和我的职业发展计划将训练我指导实验室所需的技术，重点阐明破骨细胞发育和病理性骨质破坏的机制。骨质疏松症是一种毁灭性的疾病，会导致骨骼脆弱，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。该资助旨在定义调节破骨细胞发育和功能的基因。