Role of FoxOs in Skeletal Homeostasis- Resubmission

FoxOs 在骨骼稳态中的作用 - 重新提交

基本信息

批准号：
9212784
负责人：
Maria Jose Almeida
金额：
$ 32.78万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-15 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9212784
关键词：
Acetylation Adult Adverse effects Age Age-Related Osteoporosis Aging Animals Attenuated Binding Bone Resorption Cell Line Cells DNA Deacetylase Deacetylation Degenerative Disorder Development Disease Equilibrium FOXO1A gene Foundations Funding Generations Genes Genetic Transcription Genetic study Grant Growth Factor Homeostasis Human Hydrogen Peroxide In Vitro Inherited Knowledge Laboratories Link Maintenance Malignant Neoplasms Mammals Mediating Mitochondria Mus Nerve Degeneration Non-Insulin-Dependent Diabetes Mellitus Organ Osteoblasts Osteoclasts Osteogenesis Osteoporosis Oxidative Stress Pathogenesis Pathway interactions Patients Play Population Heterogeneity Production Proteins Reactive Oxygen Species Resveratrol Role Seminal Signal Transduction Testing Tissues Up-Regulation WNT Signaling Pathway Work age effect age related attenuation beta catenin bone bone cell bone loss bone mass catalase deprivation ethnic diversity fracture risk genome-wide analysis in vivo mouse model mutant non-genetic novel therapeutics osteoclastogenesis osteoporosis with pathological fracture osteoprogenitor cell overexpression prevent progenitor protein B protein function public health relevance skeletal stressor therapeutic target therapy development transcription factor

项目摘要

DESCRIPTION (provided by applicant): Wnt/β-catenin signaling is indispensable for bone formation and the maintenance of bone mass in animals and humans. Compromised Wnt signaling plays a pathogenetic role in the development of the acquired forms of osteoporosis - not just the hereditary forms. Likewise, a decline in NAD+, Sirt1 activity and mitochondria ATP production have been implicated in several age related diseases. FoxO transcription factors attenuate Wnt signaling in lineage-committed osteoblast progenitors and, thereby, restrain their proliferation and the supply of matrix synthesizing osteoblasts. This results from the binding of FoxOs to β-catenin and the sequestration of β-catenin away from TCF-mediated transcription. Deacetylation of FoxOs by Sirt1 attenuates the binding of FoxOs to β-catenin. Thus, Sirt1 in osteoprogenitor cells increases Wnt signaling and bone formation. In addition, Wnt signaling increases ATP production via a Sirt1-dependent mechanism while FoxOs decrease ATP production. FoxOs also act in osteoclast progenitors to restrain osteoclastogenesis. This effect results from direct binding of FoxOs to DNA and upregulation of catalase gene transcription. Sirt1 stimulates FoxO-mediated transcription in osteoclast progenitors, thereby inhibiting osteoclastogenesis. The above observations form the foundation of the hypothesis that Sirt1 increases osteoblastogenesis and decreases osteoclastogenesis by deacetylating FoxOs in the respective progenitors. The age-dependent decrease in Sirt1 activity contributes to the pathogenesis of involutional osteoporosis, by tilting the balance between bone formation and resorption, in favor of the latter. Activation of Sirt1 can ameliorate these effects and may, thus, represent a rational therapeutic target for the management of osteoporosis. The beneficial effects of Sirt1 on osteoblastogenesis are amplified by increased ATP production. To test this hypothesis we will investigate the role of FoxO deacetylation in the effects of Sirt1 on bone formation and resorption using mice in which the endogenous FoxO1, 3 and 4 in osteoblast or osteoclast progenitors are replaced with FoxO1 acetylation mutant proteins; or Sirt1 is overexpressed in the presence or absence of FoxOs (Aim 1). In addition, we will examine whether stimulation of Sirt1 antagonizes the adverse effects of aging on bone using mice in which Sirt1 is overexpressed in osteoblast or osteoclast progenitors (Aim 2). Finally, we will perform in vitro studies to determine the contribution of mitochondria ATP production to osteoblastogenesis and the mechanisms via which FoxOs, Sirt1 and Wnt signaling modulate mitochondria function. This work should advance knowledge of how aging decreases bone mass. Furthermore, it should suggest novel therapies to optimize the treatment of osteoporosis.

描述（由适用提供）：Wnt/β-catenin信号传导对于骨形成和维持动物和人的骨骼量是必不可少的。受损的Wnt信号在获得的骨质疏松症形式的发展中起着致病的作用 - 不仅是遗传形式。同样，NAD+，SIRT1活性和线粒体ATP产生的下降也与几个年龄相关的疾病有关。 FOXO转录因子减弱了谱系成骨细胞祖细胞中的Wnt信号传导，从而抑制了它们的增殖和基质合成成骨细胞的供应。这是由于FOXOS与β-catenin的结合以及β-catenin从TCF介导的转录中隔离的结果。 SIRT1对FOXOS的脱乙酰化减弱了FoxOS与β-catenin的结合。那就是骨基因细胞中的SIRT1增加Wnt信号传导和骨形成。此外，WNT信号通过SIRT1依赖性机制增加了ATP的产生，而FOXOS则减少了ATP的产生。 Foxos还起作用破骨细胞祖细胞来抑制破骨细胞生成。这种作用是由于FoxoS与DNA的直接结合以及过氧化氢酶基因转录的上调。 SIRT1刺激了骨细胞祖细胞中FOXO介导的转录，从而抑制破骨细胞生成。上述观察结果构成了假说的基础，即SIRT1增加了成骨细胞生成并减少了相关祖细胞中脱乙酰基狐狸的骨质发生。 SIRT1活性的年龄依赖性降低有助于通过骨骼形成和分辨率之间的平衡，有利于后者。 SIRT1的激活可以改善这些效果，因此，代表了管理骨质疏松症的理性理论目标。 SIRT1对成骨细胞生成的有益作用通过ATP产生增加而扩大。为了检验这一假设，我们将使用小鼠使用小鼠在SIRT1对SIRT1的影响中的作用，其中内源性FOXO1、3和4在成骨细胞或破骨细胞祖细胞中被FOXO1乙酰化突变蛋白代替；或SIRT1在存在或不存在Foxos的情况下过表达（AIM 1）。此外，我们还将检查SIRT1的刺激是否会使用小鼠在成骨细胞或破骨细胞祖细胞中过表达Sirt1的小鼠对骨骼的不良反应（AIM 2）。最后，我们将进行体外研究，以确定线粒体ATP的产生对成骨细胞生成的贡献以及FOXOS，SIRT1和WNT信号调节线粒体功能的机制。这项工作应提高有关衰老如何减少骨骼的知识。此外，它应该建议优化骨质疏松症治疗的新型疗法。