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（由申请人提供）：骨质疏松症影响着 1000 万美国人，相关的脆性骨折导致显着的发病率和死亡率。骨细胞产生硬化素，这是成骨细胞骨形成的有效抑制剂，也是骨质疏松症药物的靶标。甲状旁腺激素 (PTH) 1-34（特立帕肽）可促进骨形成，部分通过减少骨细胞产生硬化素来发挥作用。这项拨款提案的重点是阐明控制骨细胞生物学的细胞内机制，重点是硬化素基因调控和作用。 IIa 类 HDAC（Hdac5 和 Hdac4）对其的控制已被确定为骨细胞硬化蛋白产生和骨细胞分化的重要调节因子。目标 1 将使用多种独立且互补的方法充分表征 IIa 类 HDAC 缺乏对体内骨细胞生物学的影响，但重要的是，目标 2 将探讨 IIa 类 HDAC 在体内 PTH 介导的硬化素抑制中的作用。关于 IIa 类 HDAC 如何控制硬化蛋白表达，目前尚不清楚，因此，目标 3 将利用尖端技术确定骨细胞中的新型 IIa 类 HDAC 结合蛋白和底物。候选人 Wein 博士是一位致力于骨骼生物学基础研究的医生/科学家。（医学博士/博士学位联合学位）为他提供了基础科学和人类生理学方面的严格培训。作为一名内分泌学家，专攻代谢性骨疾病，除了他的职业发展计划中提出的研究之外，他的临床和研究兴趣之间也存在相当大的互补性。将使他能够最大限度地利用麻省总医院内分泌科、哈佛医学院和博德研究所的资源来实现他的职业目标。他已经找到了一位导师，亨利·克罗伯格博士，他是骨骼生物学和免疫学领域的全球领导者。 PTH 的行动。Wein 博士和 Kronenberg 制定了经常会面讨论数据和职业发展的计划。Kronenberg 博士明确了 Wein 博士提出的研究的各个方面，这将构成他在 MGH 内的独立合作者的基础。已经确定了博德研究所的内分泌部门，并成立了一个咨询委员会来评估进展并规划未来的方向。Wein 博士将经常展示他的数据并参加 MGH 内分泌部门和博德研究所的研讨会和期刊俱乐部。 ,并将在每年的国际会议上展示他的发现，计划在资助写作、公开演讲和计算生物学方面开展正式课程，以进一步提高他作为独立医生/科学家的成功可能性，其中包括获得Wein 博士的长期职业目标是与他的导师 Kronenberg 博士和合作者一起在本资助提案中描述的技能，并发表第一作者手稿，以获得知名度并确立自己在骨细胞领域的地位。他自己作为一位独立研究员，研究控制体内骨细胞功能的基本细胞生物学机制，他与 Laurie Glimcher 博士合作的博士研究重点是成骨细胞生物学，但目前他需要额外的骨骼生物学培训以及研究体内和体外骨细胞的专业知识。 MGH 内分泌科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，该拨款提案的目标 1 和 2 将允许在这些领域开展工作。 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 将促进对骨细胞功能重要的新基因的发现：作为一名独立研究者，Wein 博士将利用在这笔资助中获得的技能。确定新突变株表型的建议。