Regulation of Osteoblast Differentiation by Delta FosB

描述（由申请人提供）：此竞争性修订申请将扩大当前资助的具体目标、研究设计和方法的范围，以探索成骨细胞的内在作用？骨形成中的FosB蛋白。这一扩展包括根据最近获得的数据添加一个全新的特定目标，该目标显示了？FosB和其他FosB拮抗剂以及中枢神经系统中AP1转录机制一方面调节骨形成，另一方面调节能量消耗和脂肪。我们最近部分探索了骨和脂肪表型之间的联系？在第一个资助周期中，FosB在母体资助下发表了几篇论文（Kveiborg et al., 2004; Sabatakos et al., 2000）。然而，我们最近的两项研究，一项是上个月发表的（Rowe et al., 2009），另一项是准备提交的（见附录ASBMR摘要，2009），已经产生了一些非常令人兴奋的新数据，我们认为这些数据值得进一步调查，并可能导致高度创新的发现，不仅在骨质疏松症，而且在肥胖和糖尿病方面具有重要意义。简而言之，第一项研究证明了ENO2-？具有高骨量的FosB小鼠表现出能量消耗的增加，导致脂肪细胞大小减少，从而脂肪量减少。这与降低胰岛素水平、增加胰岛素敏感性和改善葡萄糖耐量有关。自从定位以来？FosB到肥胖未能模仿表型，然后我们转向能量的中央调节。在第二项研究中，？下丘脑腹侧的FosB或构建的AP1拮抗剂（显性阴性JunD）再现了过表达的小鼠的整个表型？FosB在ENO2启动子的控制下，诱导能量消耗增加，体力活动减少，脂肪量减少，骨形成和骨量显著增加。因此，本修订应用的具体目的是确定受下丘脑表达？FosB（或工程化DNJunD）， AP1转录因子家族的拮抗剂，通过增加能量消耗和随后的脂肪量减少来强烈诱导骨形成。因此，在本应用中提出的实验可能导致鉴定调节骨形成的新途径和药物发现的新靶点，可能为骨质疏松症的合成代谢治疗干预提供新方法，但也可能为肥胖和糖尿病的病理生理学提供一些启示。

DESCRIPTION (provided by applicant): This Competitive Revision Application will expand the scope of the specific aims, research design and methods of the current grant, funded to explore the osteoblast-intrinsic role of ?FosB proteins in bone formation. This expansion consists in adding an entirely new specific aim based on recently acquired data demonstrating a role for ?FosB and other antagonists to FosB and the AP1 transcriptional machinery in the central nervous system to regulate on the one hand bone formation and on the other hand energy expenditure and fat. We have recently partially explored the link between the bone and fat phenotypes of mice overexpressing ?FosB and published a few papers under the parent grant during the first funding cycle (Kveiborg et al., 2004; Sabatakos et al., 2000). However, two of our recent studies, one published last month (Rowe et al., 2009) and one being prepared for submission (see Appendix ASBMR Abstract, 2009), have generated some very exciting new data which in our view deserve further investigation and could lead to highly innovative findings with significant implications not only in osteoporosis but also in obesity and diabetes.Briefly, the first study demonstrated that ENO2-?FosB mice, which have high bone mass, exhibited an increase in energy expenditure leading to a decrease in adipocyte size and thereby fat mass. This was associated with decreased insulin levels, increased insulin sensitivity and better glucose tolerance. Since targeting ?FosB to adiposities failed to mimic the phenotype, we then turned to the central regulation of energy. In the second study, targeted expression of ?FosB or a constructed AP1 antagonist (Dominant Negative JunD) in the ventral portion of the hypothalamus recapitulated the entire phenotype of mice overexpressing ?FosB under the control of the ENO2 promoter, inducing an increase in energy expenditure, decreased physical activity, decreased fat mass and markedly increased bone formation and bone mass. The Specific Aim of this revision application is therefore to identify the neuronal circuit(s) affected by the hypothalamic expression of ?FosB (or engineered DNJunD), antagonists of the AP1 family of transcription factors, which lead to strong induction of bone formation with an increase in energy expenditure and a subsequent reduction in fat mass. The experiments proposed in this application could therefore lead to the identification of novel pathways regulating bone formation and novel targets for drug discovery, potentially allowing new approaches for anabolic therapeutic intervention in osteoporosis, but could also shed some light on the pathophysiology of Obesity and Diabetes. PUBLIC HEALTH RELEVANCE: We have found that a protein, when expressed in a region of the brain called hypothalamus, decreases insulin in the blood, decreases fat in the body and increases the density of bones in the skeleton. We will identify how it works in the brain, potentially allowing new approaches for therapeutic intervention in osteoporosis, but this work could open new avenues for the treatment of obesity and diabetes.