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：
9026848
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/9026848
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 Foundations Funding Generations Genes Genetic Transcription Genetic study Grant Growth 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 Risk Role Seminal Signal Transduction Testing Tissues Up-Regulation Work age related attenuation beta catenin bone bone cell bone loss bone mass catalase deprivation ethnic diversity genome-wide analysis in vivo mouse model mutant non-genetic novel therapeutics osteoclastogenesis osteoporosis with pathological fracture osteoprogenitor cell overexpression prevent progenitor 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（由申请人提供）：Wnt/β-连环蛋白信号对于动物和人类的骨形成和骨量维持是不可或缺的。受损的 Wnt 信号在获得性骨质疏松症的发展中发挥着致病作用，而不仅仅是遗传性骨质疏松症。同样，NAD+、Sirt1 活性和线粒体 ATP 生成的下降与多种年龄相关疾病中的 FoxO 转录因子减弱 Wnt 信号有关。成骨细胞祖细胞，从而抑制其增殖和基质合成成骨细胞的供应，这是由于 FoxO 与 β-连环蛋白结合，并且 Sirt1 对 FoxO 的去乙酰化作用将 β-连环蛋白隔离，从而减弱了这种结合。因此，骨祖细胞中的 Sirt1 会增加 Wnt 信号传导和骨形成。此外，Wnt 信号传导还通过 a 途径增加 ATP 的产生。 Sirt1 依赖性机制，而 FoxOs 也在破骨细胞祖细胞中发挥作用，抑制破骨细胞生成。这种作用是由于 FoxOs 与 DNA 的直接结合和过氧化氢酶基因转录的上调，刺激破骨细胞祖细胞中 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以下假设的基础：Sirt1 通过使 FoxOs 脱乙酰化来增加成骨细胞生成并减少破骨细胞生成。 Sirt1 活性的年龄依赖性降低通过倾斜骨形成和吸收之间的平衡而促进骨质疏松症的发病机制，Sirt1 的激活可以改善这些影响，因此，合理的治疗靶点代表了骨质疏松症的管理，通过增加 ATP 的产生来放大 Sirt1 对成骨细胞生成的有益作用。为了验证这一假设，我们将使用小鼠研究 FoxO 去乙酰化在 Sirt1 对骨形成和骨吸收的影响中的作用。成骨细胞或破骨细胞祖细胞中的内源性 FoxO1、3 和 4 被 FoxO1 乙酰化突变蛋白替代，或者 Sirt1 在存在或存在时过度表达；此外，我们将使用 Sirt1 在成骨细胞或破骨细胞祖细胞中过度表达的小鼠来检查 Sirt1 的刺激是否可以拮抗衰老对骨骼的不利影响（目标 2）。研究确定线粒体 ATP 生成对成骨细胞生成的贡献以及 FoxOs、Sirt1 和 Wnt 信号传导调节线粒体功能的机制。这项工作应该增进人们对衰老如何进行的了解。此外，它应该提出新的疗法来优化骨质疏松症的治疗。