PKC delta as a central mediator of osteogenic signaling

PKC δ 作为成骨信号传导的中心介质

基本信息

批准号：
8528895
负责人：
Atum Buo
金额：
$ 2.83万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8528895
关键词：
Address Affect Age Alkaline Phosphatase Anabolic Agents Applications Grants Biological Assay Bone Density Bone Growth Bone Marrow Calcium Cells Cellular biology Commit DNA Binding Defect Deposition Development Dinoprostone Disease Electrophoretic Mobility Shift Assay Embryo Exhibits Fibroblast Growth Factor 2 Figs - dietary Future Gene Expression Genes Genetic Models Genetic Recombination Glean Goals Grant Health Hormones In Vitro Knock-out Knockout Mice Knowledge Limb structure Mediating Mediator of activation protein Mesenchymal Messenger RNA Metabolic Bone Diseases Molecular Molecular Biology Molecular Target Mus Names Osteoblasts Osteoclasts Osteogenesis Osteoporosis Parathyroid gland Pathway interactions Phenotype Protein Isoforms Proteins Regulation Research Role Serine/Threonine Phosphorylation Signal Pathway Signal Transduction Signaling Molecule Societies Staining method Stains Stromal Cells Technology Testing Therapeutic Intervention Work attenuation bone bone loss bone mass bone quality chromatin immunoprecipitation combat design disability in vivo mineralization novel offspring osteoblast differentiation osteogenic osteoprogenitor cell progenitor protein kinase C-delta public health relevance restoration skeletal therapeutic target therapy design transcription factor

项目摘要

DESCRIPTION (provided by applicant): Diseases of low bone mass, particularly osteoporosis, have gravely impacted society, causing massive disability. Current therapies for the restoration of bone mass are limited and focus primarily on the attenuation of osteoclast activity. The development of anabolic therapies that stimulate osteoblast activity and bone mass acquisition is essential; however, our understanding of the underlying mechanisms regulating osteogenic differentiation and bone formation is still incomplete. The work proposed in this grant aims to expand on our knowledge of the molecular mechanisms involved in bone mass acquisition by assessing the role of protein kinase C delta (PKC¿) in bone. Although PKC¿-/- mice exhibit reduced embryonic bone formation and a cell autonomous defect in osteoblast differentiation from embryonic limb primordial cultures, indicating involvement of PKC¿ in embryonic osteogenesis, a role for PKC¿ in post-natal osteoblast function and the molecular targets of PKC¿ action in skeletal cells have not been established. Our lab has shown that PKC¿ regulates the Runx2 activity, one of the master regulators of osteogenesis, thereby presenting a possible mechanism by which PKC¿ can impact osteogenic differentiation. The central hypothesis of this grant application is that that PKC¿ is a critical factor in multiple signaling cascades that converge on Runx2 and promote osteogenesis and increased bone formation. There are two specific aims to address this hypothesis. (Specific Aim 1) To examine the effect of PKC¿ deficiency on osteoanabolic signaling downstream of multiple pro-osteogenic factors in vitro. (Specific Aim 2) To characterize the in vivo impact of loss of PKC¿ in the cells of the osteoblastic lineage on post-natal bone formation. Cell and molecular biology, as well as in vivo genetic models, will be used to resolve key knowledge gaps regarding the role of PKC¿ in bone. Defining these mechanisms will provide critical understanding into how PKC¿ ultimately affects osteoblast function and bone mass acquisition. Hopefully, the knowledge gleaned from these studies will aid in the development of rational therapies against low bone mass disorders that stimulate the formation of bone by targeting pathways that converge on Runx2 via PKC¿ modulation.

描述（由适用提供）：低骨量的疾病，尤其是骨质疏松症，对社会产生了严重影响，导致了大规模的残疾。当前的骨骼恢复疗法受到限制，主要集中于破骨细胞活性的衰减。刺激成骨细胞活性和骨质量获取的合成代谢疗法的发展至关重要。但是，我们对基本机制调节成骨分化和骨形成的理解仍然不完整。这项赠款中提出的工作旨在通过评估蛋白激酶C三角洲（PKC®）在骨骼中的作用来扩展我们对参与骨骼量的分子机制的了解。尽管PKC�-/ - 小鼠暴露了胚胎骨的形成减少和成骨细胞与胚胎肢体原始培养物的分化中的细胞自主缺陷，这表明PKC涉及胚胎成生成，这是PKC的作用，PKC的作用是PKC的作用，在pKC中的作用是PKC的作用，而PKC构建了PKC的作用。我们的实验室表明，PKC»调节runx2活性是成骨的主要调节剂之一，从而提出了一种可能影响骨化分化的可能机制。该赠款应用的中心假设是，PKC¿是多种信号级联反应的关键因素，该级联对Runx2收敛并促进骨生成并增加骨形成。有两个具体的目的来解决这一假设。（特定目的1）检查PKC不足对体外多种促稳态因子下游骨代谢信号的影响。（特定目的2）表征成骨细胞谱系细胞中PKC丢失对产后骨形成的体内影响。细胞和分子生物学以及体内遗传模型将用于解决有关PKC骨骼作用的关键知识差距。定义这些机制将为PKC缺如何影响成骨细胞功能和骨骼质量获取提供批判性理解。希望从这些研究中清除的知识将有助于开发针对低骨质量疾病的理性疗法，这些疗法通过靶向通过PKC¿调制在Runx2上汇聚的途径来刺激骨骼的形成。