Functions of the PH-Domain Leucine Rich Protein Phosphatase (Phlpp)1 in Osteoclasts

PH 结构域富含亮氨酸的蛋白磷酸酶 (Phlpp)1 在破骨细胞中的功能

基本信息

批准号：
9761459
负责人：
Elizabeth W Bradley
金额：
$ 33.22万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-21 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761459
关键词：
Acetylation Address Affect Age Aging Alleles American Animals Arthritis Attenuated Binding Biochemical Biological Assay Bone Density Bone Diseases Bone Resorption Bone remodeling CSF1R gene Cell Nucleus Cells Chemicals Control Animal Cytoplasm Data Developed Countries Developing Countries Disease Economic Burden Enterobacteria phage P1 Cre recombinase Epigenetic Process Estrogen Replacements Estrogen Therapy Estrogens Event Exhibits Fracture Fright Genetic Transcription Goals Healthcare Systems Hip Fractures Histones Hospitalization Human In Vitro Individual Knock-out Knockout Mice Knowledge Leucine LoxP-flanked allele Macrophage Colony-Stimulating Factor Maintenance Measures Modeling Molecular Morbidity - disease rate Mus Nuclear Operative Surgical Procedures Osteoclasts Osteogenesis Osteopenia Osteoporosis Ovariectomy PH Domain Pathway interactions Periodontitis Phenotype Phosphorylation Population Process Protein phosphatase Publishing Quality of life Receptor Protein-Tyrosine Kinases Role Serious Adverse Event Stem cells Testing Translating United States Woman Work X-Ray Computed Tomography base bone bone mass cortical bone fracture risk high risk in vivo innovation men mortality mutant novel osteoclastogenesis osteoporosis with pathological fracture progenitor promoter protective effect public health relevance reconstitution response social substantia spongiosa tumor

项目摘要

Abstract Osteoporosis is a significant cause of morbidity and mortality in developed countries. In the United States, over 8 million women and 2 million men age 50 and above have osteoporosis. Another 51 million women and 35 million men have osteopenia. This translates into a higher risk of fracture within this population, with half of all women and one quarter of men projected to suffer a low bone mass-related fracture. Osteoporotic fractures impart deleterious consequences, including increased hospitalization and mortality. An estimated 25% of individuals will die within one year of a hip fracture. Despite the availability of anti-resorptive therapies that decrease fracture rates, their prescription and use have declined significantly due to fears of extremely rare but serious adverse events. This has created a treatment gap that threatens the quality of life of millions of Americans and poses a tremendous challenge to our healthcare systems and economy. It also highlights the need to better understand osteoclast formation and function. The goal of this five-year application is to determine the role of the protein phosphatase Phlpp1 in osteoclastogenesis and bone density and to define the epigenetic mechanisms required for Phlpp1 to modulate Csf1r (c-fms) expression and osteoclastogenesis. The five-year deliverables are: 1) definition of the functions of Phlpp1 in osteoclast progenitor cells, 2) characterization of the cytosolic functions of Phlpp1 that influence M-CSF responsiveness, Csfr1 expression and osteoclast function, and 3) determination of the nuclear functions of Phlpp1 that influence Csfr1 transcription and osteoclastogenesis. This work will increase our understanding of how Phlpp1 and associated pathways affect bone density.

抽象的骨质疏松症是发达国家发病率和死亡率的重要原因。在美国， 800万妇女和2000岁及以上的男性患有骨质疏松症。另外5100万妇女和35名百万男性患有骨质减少。这转化为该人群中骨折的较高风险，其中一半妇女和四分之一的男性预计会遭受与骨质量相关的骨折。骨质疏松骨折带来有害后果，包括增加住院和死亡率。估计的25％个人将在髋部骨折的一年内死亡。尽管有可用的抗高压疗法由于担心极为罕见，但严重的不利事件。这产生了一个治疗差距，威胁着数百万的生活质量美国人并对我们的医疗保健系统和经济构成了巨大挑战。它还突出了需要更好地了解破骨细胞的形成和功能。该五年申请的目的是确定蛋白质磷酸酶PHLPP1在破骨细胞生成和骨密度中的作用，并定义 PHLPP1调节CSF1R（C-FMS）表达和破骨细胞生成所需的表观遗传机制。这五年可交付成果是：1）PHLPP1在破骨细胞祖细胞中的功能的定义，2）影响M-CSF响应性的PHLPP1的胞质功能的表征CSFR1表达和破骨细胞功能，以及3）测定影响CSFR1的PHLPP1的核功能转录和破骨细胞生成。这项工作将增加我们对PHLPP1和相关方式的理解途径会影响骨密度。