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：
9261481
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/9261481
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 Future Gene Expression Regulation Genes Goals Grant Histone Deacetylase Homeostasis Human Immature Bone In Vitro Institutes International Investigation Ions Journals Knowledge Manuscripts Mediating Mentors Metabolic Bone Diseases Metabolism 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 Pharmacology Phenotype Physicians Physiology Play Probability Production Proliferating Proteomics Public Speaking Publishing Receptor Signaling Recombinants Regulation Research Research Personnel Research Proposals Resources Role Scientist TNFSF11 gene Techniques Testing Training Work Writing aging population bone bone cell bone mass bone strength career career development cell type cellular targeting cost density drug efficacy experience fragility fracture human disease improved in vivo inhibitor/antagonist interest mechanical force medical schools meetings mortality mutant novel osteoclastogenesis public health relevance 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（由适用提供）：骨质疏松症影响1000万美国人，相关的脆弱性碎片会导致显着的发病率和死亡率。尽管对控制成骨细胞和破骨细胞功能的分子途径有很多了解，但对骨骼中最丰富的细胞类型，骨细胞中最丰富的细胞类型知之甚少。骨细胞产生硬化素，这是成骨细胞和骨质疏松药物靶标的骨形成的潜在抑制剂。值得注意的是，唯一现有的骨质疏松疗法促成骨骼形成，甲状旁腺骑马酮（PTH）1-34（Teriparatide）（teriparatide），部分作用是通过减少骨细胞的硬化蛋白产生。该赠款提案的重点是阐明控制骨细胞生物学的细胞内机制，重点是硬化蛋白基因调节及其控制PTH。 IIA类HDAC（HDAC5和HDAC4）一般来说，已确定为骨细胞硬化蛋白产生和骨细胞分化的重要调节剂。 AIM 1将使用多种独立和完整的方法充分表征IIA类HDAC缺乏对体内骨细胞生物学的影响。 AIM 2将询问IIA类HDAC在体内PTH介导的硬化蛋白抑制中的作用。重要的是，尽管已经知道一些有关IIA类HDAC如何控制硬化蛋白表达的信息，但仍然未知。因此，AIM 3将使用最先进的蛋白质组学方法确定骨细胞中新型IIA HDAC结合蛋白和底物。候选人Wein博士是一位物理/科学家，致力于从事骨骼生物学基础研究的职业。他的教育（合并的MD/PHD学位）为他提供了基础科学和人类生理学的严格培训。内分泌学家在代谢骨疾病中的特性化，其临床和研究兴趣之间存在相当大的补充重叠。除了内部提出的研究之外，Wein博士的职业发展计划还可以使他最大程度地利用MGH内分泌部门，哈佛医学院和广泛研究所中的资源，以实现其职业目标。他确定了一种心态，亨利·克朗伯格（Henry Kronenberg）博士是骨骼生物学和PTH行动的全球领导者。 Wein博士和Kronenberg博士有一个经常会议讨论数据和职业发展的计划。克罗南伯格（Kronenberg）博士清楚地确定了Wein博士提出的研究的各个方面，该研究将构成他独立职业的基础。已经确定了MGH内分泌部门和广大研究所内的合作者，并且已经成立了咨询委员会来评估进度并计划未来的方向。 Wein博士将经常介绍他的数据，并参加MGH内分泌部门和Broad Institute的Semians和期刊俱乐部，并将每年在国际会议上介绍他的发现。计划在赠款写作，公开演讲和计算生物学方面计划正式课程，以进一步提高他作为独立的Wein博士的直接职业目标的成功可能性，包括获取该赠款提案中所描述的技能，并与他的心理Kronenberg博士和在其中确定的合作者和合作者一起确定，并出版了第一名作者手稿，以获得名称认可和在该领域中建立自己的领域。 Wein博士的长期职业目标是将自己确立为一名独立研究者，研究了控制体内骨细胞功能的基本细胞生物学机制。他与劳里·格林彻（Laurie Glimcher）博士的博士学位专注于成骨细胞生物学，但此时他需要在体内和体外研究骨骼生物学和研究骨细胞的其他培训。 MGH内分泌单元中存在着大量的专业知识，该部门是一个致力于矿物离子代谢和骨骼生物学的协作群体，并密切关注与对人类疾病的理解和治疗有关。该赠款提案的目标1和2将使Wein博士能够在研究骨细胞生物学所需的体内方法中获得经验和专业知识。 AIM 3将促进发现对骨细胞功能重要的新基因的发现：作为独立研究者，Wein博士将使用本赠款建议中获得的技能来确定新型突变菌株的表型。