Cross-talk between skeleton and pancreas morphogeneses during development

发育过程中骨骼和胰腺形态发生之间的串扰

• 批准号: 8806907
• 负责人: Patricia Florence Ducy
• 金额: $ 21.12万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8806907
• 关键词: Address; Adult; Affect; Agreement; Biological Markers; Biology; Bone Development; Bone Resorption; Cell Proliferation; Cell Proliferation Regulation; Cell physiology; Cells; Data; Defect; Development; Diet; Embryo; Embryonic Development; Fatty acid glycerol esters; G-Protein-Coupled Receptors; Gene Expression; Genotype; Glucose; Goals; Hormones; Human; Insulin; Islets of Langerhans; Link; Mediating; Methods; Molecular; Morphogenesis; Mothers; Mouse Strains; Mus; Organ; Osteoblasts; Osteocalcin; Osteoclasts; Pancreas; Phenotype; Placenta; Play; Pregnancy; Process; Production; Receptor Signaling; Regulation; Role; Serum; Severities; Signal Transduction; Skeleton; Testing; TimeLine; base; bone; bone cell; bone metabolism; feeding; glucose metabolism; in vivo; insulin secretion; insulin signaling; meetings; mouse model; novel; offspring; osteoblast differentiation; pancreas development; progenitor; public health relevance; pup; skeletogenesis; transcription factor

DESCRIPTION (provided by applicant): This project has two, intrinsically linked, goals. The first one is to identify cross-regulatory mechanisms between bone and pancreas morphogenesis during development. The second one is to assess whether this cross-regulation involves a maternal component. A growing body of studies has established the existence of a cross-talk of glucose and bone metabolisms during adulthood. On the one hand osteoblasts, the bone-forming cells, secrete a hormone, osteocalcin, regulating insulin synthesis and secretion among other processes. On the other hand, insulin signaling in osteoblasts regulates osteocalcin production and its resorption-mediated activation. Hence, during adulthood there is a feed-forward regulatory loop whereby insulin secretion by b-cells enhances the production and activity of osteocalcin, which in turns promotes insulin synthesis. More recently, we have shown that osteocalcin also controls b-cell proliferation in the developing embryo. Drawing a parallel with the functional crosstalk between bone cells and b-cells existing in adults, we hypothesize that a regulatory loop between osteocalcin and insulin could exist during development and could contribute to the formation of the skeleton and endocrine pancreas in the embryo. Accordingly, pups lacking insulin signaling in osteoblasts have a decrease in b-cell proliferation and lower serum levels of a biomarker of bone resorption compared to control littermates. Another recently identified feature of osteocalcin is its ability to cross the placenta during pregnancy and reach the embryo before it can produce its own. Hence, maternal osteocalcin could play a role in regulating insulin production and b- cell proliferation during pancreas development. In agreement with this hypothesis we have observed that adult Ocn+/- mice fed a high fat diet become more glucose intolerant when they are born from an Ocn-/- mother than from an Ocn+/- mother. Taken together, these novel findings and our preliminary data raise the prospect that maternal osteocalcin could initiate, or contribute to, a cross-regulation between osteocalcin and insulin that influences bone and pancreas development. To demonstrate this hypothesis we propose the following Specific Aims: 1. To determine whether maternal osteocalcin influences insulin production and b-cell proliferation in the embryo 2. To test whether insulin signaling in osteoblasts contributes to the regulation of b-cell proliferation by osteocalcin during development 3. To assess whether skeletogenesis is dependent of the embryonic production of insulin during development We would like to emphasize here that the genetically modified mouse models required to perform these studies have already been generated and therefore that achieving these aims can meet the timeline of a R21 project.

描述（由申请人提供）：本项目有两个内在联系的目标。第一个是确定发育过程中骨和胰腺形态发生的交叉调控机制。第二个是评估这种交叉调节是否涉及母体成分。越来越多的研究已经证实，在成年期存在葡萄糖和骨代谢的串扰。一方面，成骨细胞，骨形成细胞，分泌一种激素，骨钙素，调节胰岛素的合成和分泌等过程。另一方面，成骨细胞中的胰岛素信号调节骨钙素的产生及其吸收介导的激活。因此，在成年期存在一个前馈调节循环，即b细胞分泌胰岛素增强骨钙素的产生和活性，骨钙素反过来促进胰岛素合成。最近，我们已经证明骨钙素也控制发育中的胚胎中的b细胞增殖。与成人骨细胞和b细胞之间的功能串音相似，我们假设骨钙素和胰岛素之间的调节回路可能在发育过程中存在，并可能有助于胚胎骨骼和内分泌胰腺的形成。因此，与对照组相比，成骨细胞中缺乏胰岛素信号的幼崽b细胞增殖减少，骨吸收生物标志物的血清水平降低。最近发现的骨钙素的另一个特征是，它能够在怀孕期间穿过胎盘，在胚胎产生自己的胎盘之前到达胚胎。因此，在胰腺发育过程中，母体骨钙素可能在调节胰岛素产生和b细胞增殖中发挥作用。与这一假设一致，我们观察到，与Ocn+/-母鼠相比，Ocn+/-母鼠在高脂肪饮食中出生时，葡萄糖耐受性更差。综上所述，这些新发现和我们的初步数据表明，母体骨钙素可能启动或促成骨钙素和胰岛素之间的交叉调节，从而影响骨骼和胰腺的发育。为了证明这一假设，我们提出以下具体目标：1。确定母体骨钙素是否影响胚胎中胰岛素产生和b细胞增殖2。研究成骨细胞中的胰岛素信号是否参与骨钙素在发育过程中对b细胞增殖的调节。为了评估骨骼形成是否依赖于发育过程中胰岛素的胚胎产生，我们想在这里强调，进行这些研究所需的转基因小鼠模型已经产生，因此实现这些目标可以满足R21项目的时间表。