Novel regulatory mechanisms of the osteoclast transcriptional program

破骨细胞转录程序的新调控机制

• 批准号: 7385293
• 负责人: ANTONIOS O ALIPRANTIS
• 金额: $ 13.09万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 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/7385293
• 关键词: Adult; Albers-Schonberg disease; Alleles; American; Biology; Biomedical Research; Bone Resorption; Cardiac; Cells; Clinic; Commit; Communities; Condition; 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; NF-AT; New York; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Pathogenesis; Pathologic; Pathway interactions; Phase; Physiological; Pliability; Postdoctoral Fellow; Process; RNA; RNA Interference; Rate; Repression; Rheumatoid Arthritis; Rheumatology; Role; Signaling Molecule; Skeletal system; Skeleton; Students; System; TNFSF11 gene; Techniques; Technology; Tissues; Training; Tumor necrosis factor receptor 11b; Universities; Vertebrates; Work; base; bone; career; clinically relevant; college; 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 disorder; therapeutic target; transcription factor

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，我致力于研究对细菌病原体的先天免疫反应。在2001年以优异的成绩完成医学院的学业后，我接受了内科和流变学的培训。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（Dr. Laurie Glimcher）进行博士后研究。在格里姆彻博士的实验室里，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，如骨质疏松症和炎性关节炎。活化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，并与破骨细胞生成有关。我们使用Cre-loxP技术产生了NFATd的鼠条件性敲除。NFATd的缺失导致骨硬化症和破骨细胞生成缺陷。在目的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索NFATd在破骨细胞中的作用。我们最近发现，在缺乏NFATd的情况下，破骨细胞前体产生破骨细胞分化的有效抑制剂--骨保护素。在目标2中，探讨了这一观察结果的机制和后果。最后，利用RNAi技术的高通量筛选已经开始鉴定破骨细胞分化的新调节剂。目标3试图验证在初始屏幕中确定的“命中”，并生成一个目标列表，以便在我职业生涯的紧迫阶段进行探索。Glimcher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场所。骨骼生物学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掌握指导实验室所需的技术，该实验室的重点是阐明破骨细胞发育和病理性骨破坏的机制。骨质疏松症是一种破坏性的疾病，导致骨质疏松，折磨着数百万美国人。破骨细胞是唯一能够破坏骨骼的细胞。该基金旨在确定调节破骨细胞发育和功能的基因。