权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Dissecting the roles of class IIa HDACs in osteocyte biology

剖析 IIa 类 HDAC 在骨细胞生物学中的作用

基本信息

批准号：
9041522
负责人：
Marc Nathan Wein
金额：
$ 16.46万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9041522
关键词：
Advisory Committees Affect American Applications Grants Area Attention Basic Science Binding Proteins Biochemical Biology Bone Matrix Bone Resorption Cell physiology Cells Cellular biology Clinical Research Computational Biology Data Development Plans Doctor of Philosophy Drug Design Drug Targeting Drug usage Education Endocrine Endocrinologist Equilibrium FDA approved Forteo Fracture Future Gene Expression Regulation Genes Goals Grant Health Histone Deacetylase Histones Homeostasis Human Immature Bone In Vitro Institutes International Investigation Ions Journals Knowledge Manuscripts Mechanics Mediating Mentors Metabolic Bone Diseases Methodology Minerals Mitotic Molecular Morbidity - disease rate Mus Names New Agents Osteoblasts Osteocalcin Osteoclasts Osteocytes Osteogenesis Osteopenia Osteoporosis PTH gene Parathyroid Hormone Receptor Parathyroid Hormone Receptors Pathway interactions Phenotype Physicians Physiology Play Probability Production Proliferating Proteomics Public Speaking Publishing Recombinants Regulation Research Research Personnel Research Proposals Resources Role Scientist Signal Transduction TNFSF11 gene Techniques Testing Training Work Writing aging population base bone bone cell bone mass bone metabolism bone strength career career development cell type cellular targeting cost density experience human disease improved in vivo inhibitor/antagonist interest medical schools meetings mortality mutant novel osteoclastogenesis response skeletal skills success

项目摘要

DESCRIPTION (provided by applicant): Osteoporosis affects 10 million Americans, and associated fragility fractures cause significant morbidity and mortality. While a great deal is known about the molecular pathways controlling osteoblast and osteoclast function, relatively little is known about the most abundant cell type in bone, the osteocyte. Osteocytes produce sclerostin, a potent inhibitor of bone formation by osteoblasts and an osteoporosis drug target. Notably, the only existing osteoporosis therapy that boosts bone formation, parathyroid hormone (PTH) 1-34 (teriparatide), works in part by reducing sclerostin production by osteocytes. The focus of this grant proposal is to elucidate the intracellular mechanisms controlling osteocyte biology, with an emphasis on sclerostin gene regulation and its control by PTH. Class IIa HDACs (Hdac5 and Hdac4) have been identified as important regulators of osteocytic sclerostin production and osteocyte differentiation in general. Aim 1 will fully characterize the effects of class IIa HDAC deficiency on osteocyte biology in vivo using multiple independent and complementary approaches. Aim 2 will interrogate the role of class IIa HDACs in PTH-mediated sclerostin suppression in vivo. Importantly, though some information is known about how class IIa HDACs might control sclerostin expression, much remains unknown. Therefore, Aim 3 will determine novel class IIa HDAC binding proteins and substrates in osteocytes using cutting-edge proteomic approaches. The candidate Dr. Wein is a physician/scientist dedicated to a career in basic investigation in skeletal biology. His education (combined MD/PhD degrees) provides him rigorous training in basic science and human physiology. An endocrinologist subspecializing in metabolic bone diseases, considerable and complementary overlap exists between his clinical and research interests. Beyond the research proposed within, Dr. Wein's career development plan will allow him to maximize the resources within the MGH Endocrine Unit, Harvard Medical School, and the Broad Institute to achieve his career goals. He has identified a mentor, Dr. Henry Kronenberg, who is a worldwide leader in skeletal biology and PTH actions. Dr. Wein and Kronenberg have a plan for frequent meetings to discuss data and career development. Dr. Kronenberg has clearly identified aspects of the research proposed by Dr. Wein which will form the basis of his independent career. Collaborators within the MGH Endocrine Unit and at the Broad institute have been identified, and an advisory committee has been formed to evaluate progress and plan future directions. Dr. Wein will frequently present his data and attend seminars and journal clubs in the MGH Endocrine Division and at the Broad Institute, and will present his findings at international meetings on an annual basis. Formal coursework is planned in grant writing, public speaking, and computational biology to further enhance his probability of success as an independent physician/scientist. Dr. Wein's immediate career goals include acquiring the skills described in this grant proposal in conjunction with his mentor Dr. Kronenberg and collaborators identified within, and publishing first authors manuscripts in order to gain name recognition and to establish himself in the osteocyte field. Dr. Wein's long-term career goal is to establish himself as an independent investigator studying basic cell biology mechanisms controlling bone cell function in vivo. His PhD work with Dr. Laurie Glimcher focused on osteoblast biology, but at this point he needs additional training in skeletal biology and studying osteocytes in vivo and in vitro. Substantial expertise in these areas is present within MGH Endocrine Unit, a collaborative group dedicated to mineral ion metabolism and bone biology, with close attention to relevance to the understanding and treatment of human disease. Aims 1 and 2 of this grant proposal will allow Dr. Wein to gain experience and expertise in the in vivo approaches required to study osteocyte biology. Aim 3 will facilitate the discovery of new genes important for osteocyte function: as an independent investigator, Dr. Wein will then use the skills acquired in this grant proposal to determine the phenotype of novel mutant strains.

描述（由申请人提供）：骨质疏松症影响1000万美国人，相关的脆性骨折导致显著的发病率和死亡率。虽然人们对控制成骨细胞和破骨细胞功能的分子途径了解很多，但对骨骼中最丰富的细胞类型骨细胞却知之甚少。骨细胞产生硬化素，一种成骨细胞骨形成的有效抑制剂和骨质疏松症药物靶点。值得注意的是，唯一现有的促进骨形成的骨质疏松症治疗，甲状旁腺激素（PTH）1-34（teriparthaline），部分通过减少骨细胞产生硬化素来起作用。本基金的重点是阐明骨细胞生物学的细胞内控制机制，重点是骨硬化素基因调控及其由甲状旁腺素控制。IIa类HDAC（Hdac 5和Hdac 4）已被鉴定为一般骨细胞硬化素产生和骨细胞分化的重要调节剂。目的1将使用多种独立和互补的方法充分表征IIa类HDAC缺陷对体内骨细胞生物学的影响。目的2将询问IIa类HDAC在体内PTH介导的硬化素抑制中的作用。重要的是，尽管关于IIa类HDAC如何控制sclerostin表达的一些信息是已知的，但仍有许多未知数。因此，目标3将确定新的IIa类HDAC结合蛋白和底物的骨细胞使用尖端的蛋白质组学方法。Wein博士是一名医生/科学家，致力于骨骼生物学基础研究的职业生涯。他的教育（结合MD/博士学位）为他提供了基础科学和人体生理学的严格培训。作为一名代谢性骨病的内分泌学家，他的临床和研究兴趣之间存在着相当大的互补性重叠。Wein博士的职业发展计划将使他能够最大限度地利用MGH内分泌科、哈佛医学院和布罗德研究所的资源，以实现他的职业目标。他已经确定了一位导师，亨利Kronenberg博士，谁是骨骼生物学和PTH行动的全球领导者。Wein博士和Kronenberg有一个经常开会讨论数据和职业发展的计划。Kronenberg博士已经清楚地确定了Wein博士提出的研究的各个方面，这些方面将成为他独立职业生涯的基础。已经确定了MGH内分泌股和布罗德研究所的合作者，并成立了一个咨询委员会，以评估进展情况和规划未来的方向。Wein博士将经常展示他的数据，并参加MGH内分泌部和布罗德研究所的研讨会和期刊俱乐部，并将每年在国际会议上展示他的研究结果。正式的课程计划在补助金写作，公开演讲和计算生物学，以进一步提高他作为一个独立的医生/科学家成功的概率。Wein博士的近期职业目标包括与他的导师Kronenberg博士和其中确定的合作者一起获得本资助提案中描述的技能，并出版第一作者的手稿，以获得知名度并在骨细胞领域建立自己的地位。Wein博士的长期职业目标是成为一名独立的研究者，研究控制体内骨细胞功能的基本细胞生物学机制。他与劳里Glimcher博士的博士工作集中在成骨细胞生物学，但在这一点上，他需要额外的培训骨骼生物学和研究骨细胞在体内和体外。MGH内分泌单位是一个致力于矿物离子代谢和骨生物学的合作小组，密切关注与人类疾病的理解和治疗的相关性。本拨款提案的目标1和2将使Wein博士获得研究骨细胞生物学所需的体内方法的经验和专业知识。目标3将促进发现对骨细胞功能重要的新基因：作为一名独立的研究者，Wein博士将利用这项资助提案中获得的技能来确定新突变株的表型。