Mechanisms of Alcohol-Induced Hepatic Osteodystrophy

酒精性肝性骨营养不良的机制

基本信息

批准号：
8969937
负责人：
YASUKO IWAKIRI
金额：
$ 24.08万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-05 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8969937
关键词：
Adipocytes Alcohol abuse Alcohol consumption Alcohol dependence Alcohols Biology Bone Diseases Bone Growth Boxing Cell Differentiation process Cells Chronic Collaborations Data Development Diet Disease Ethanol Fracture Gene Mutation Generations Genes Goals Hepatic Homeostasis Hormonal Human Knockout Mice Lead Light Liver Mediating Mendelian disorder Mesenchymal Stem Cells Modeling Mus Nutritional Osteoblasts Osteogenesis Osteogenesis Imperfecta PPAR gamma Pathway interactions Patients Phenotype Physiologic calcification Pluripotent Stem Cells Proteins Publishing Regulation Risk Signal Pathway Signal Transduction Source Specimen Stem cells Testing base beta catenin bone bone cell bone loss demineralization feeding human disease induced pluripotent stem cell inhibitor/antagonist knock-down member novel null mutation osteoblast differentiation pigment epithelium-derived factor problem drinker public health relevance receptor response restoration skeletal stem cell differentiation substantia spongiosa transcription factor

项目摘要

DESCRIPTION (provided by applicant): Chronic alcohol abuse predisposes to bone fractures but why this happens is unclear. Nutritional and hormonal deficiencies have been postulated to increase fracture risk but studies comparing alcoholics to healthy controls have often not shown significant differences. Thus, other factors are likely involved. A critical feature of bone homeostasis is the need for continual differentiation of stem cells to osteoblasts, the cells responsible for new bone formation. Single gene diseases that impact bone integrity can shed light on novel factors that regulate stem cell differentiation to osteoblasts. Recently, gene mutations that result in complete absence of pigment epithelium-derived factor (PEDF) have been identified as the cause of Osteogenesis Imperfecta (OI) Type VI, an autosomal recessive disease characterized by severely weakened bone and early fractures. We previously published that PEDF KO mice recapitulate the human OI Type VI phenotype with marked trabecular bone loss in young mice. We further showed that PEDF directs a key signaling pathway that is responsible for stem cell differentiation to osteoblasts and away from adipocytes. Based on this human disease, we have defined PEDF as a novel osteoblast differentiation factor. The studies outlined in this application will investigate whether PEDF can rescue the bone loss that occurs in two well-characterized models of alcohol feeding. We will also investigate the signaling pathways that mediate new osteoblast formation. Finally, we have collaborations with clinicians who have OI Type V and VI patients. Inducible pluripotent stem cells will be created from these patients. We will then assess whether these PEDF-null stem cells can differentiate normally to bone cells. Findings from this application may be helpful in defining molecules that can mimic PEDF's actions on bone cell differentiation.

描述（由申请人提供）：长期酗酒容易导致骨折，但为什么会发生这种情况尚不清楚。营养和激素缺乏被认为会增加骨折风险，但将酗酒者与健康对照组进行比较的研究通常没有显示出显着差异。骨稳态的一个关键特征是干细胞不断分化为成骨细胞，影响骨完整性的单基因疾病可以揭示这一点。最近，导致色素上皮衍生因子（PEDF）完全缺失的基因突变已被确定为 VI 型成骨不全症（OI）的原因，这是一种常染色体隐性遗传病，其特征为我们之前发表过 PEDF KO 小鼠重现了年轻小鼠中明显的小梁骨丢失的人类 OI 型表型。 PEDF 负责干细胞分化为成骨细胞并远离脂肪细胞，基于这种人类疾病，我们将 PEDF 定义为一种新型成骨细胞分化因子。本申请中概述的研究将研究 PEDF 是否可以挽救两种情况下发生的骨质流失。我们还将研究介导新成骨细胞形成的信号通路。然后，我们将评估这些 PEDF 无效的干细胞是否可以正常分化为骨细胞。该应用的发现可能有助于定义可以模拟 PEDF 对骨细胞分化作用的分子。