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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：
10237904
负责人：
Elizabeth W Bradley
金额：
$ 30.91万
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10237904
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 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 Testing Translating United States Wild Type Mouse Woman Work base bone bone mass conditional knockout cortical bone fracture risk high risk in vivo innovation men microCT mortality mutant novel osteoclast progenitor osteoclastogenesis osteoporosis with pathological fracture promoter protective effect public health relevance reconstitution response social stem cells 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.

摘要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，结束了 800万50岁及以上的女性和200万男性患有骨质疏松症。另有5100万名女性和35名有数百万男性患有骨质疏松症。这转化为该人群中更高的骨折风险，有一半的人女性和四分之一的男性预计会遭受与低骨量相关的骨折。骨质疏松性骨折造成有害后果，包括增加住院和死亡率。估计有25%的人个人将在髋部骨折后一年内死亡。尽管有抗吸收疗法可用，降低骨折发生率，他们的处方和使用已经显著下降，因为担心极其罕见但严重的不良事件。这造成了一个治疗缺口，威胁到数百万人的生活质量并对我们的医疗体系和经济构成了巨大的挑战。它还突出了需要更好地了解破骨细胞的形成和功能。这项为期五年的申请的目标是确定蛋白磷酸酶PHLPP1在破骨细胞形成和骨密度中的作用，并确定 PHLPP1调节CSF1R(c-FMS)表达和破骨细胞生成所需的表观遗传学机制。这个五年的交付成果是：1)PHLPP1在破骨细胞前体细胞中的功能定义，2) 影响M-CSF反应性和Csfr1表达的PHLPP1的胞浆功能特征和破骨细胞功能，以及3)影响Csfr1的PHLPP1核功能的测定转录和破骨细胞发生。这项工作将增加我们对PHLPP1和关联的理解途径会影响骨密度。