Lrp5-Dependent Regulation of Bone Mass Accrual by Gut-Derived Serotonin

肠道来源的血清素对骨量增长的 Lrp5 依赖性调节

基本信息

批准号：
8291417
负责人：
Gerard Karsenty
金额：
$ 36.41万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8291417
关键词：
Accounting Affect Aging Anabolism Animals Belief Biological Assay Birth Bone Diseases Bone remodeling CREB1 gene Cells Data Development Disease Drosophila Arrow protein Duodenum Endocrine Endocrine System Diseases Enterochromaffin Cells Enzymes Funding Genes Genetic Homologous Gene Hormones Human LDL-Receptor Related Proteins Light Maintenance Mediating Mediator of activation protein Methodology Microarray Analysis Molecular Molecular Abnormality Mus Mutant Strains Mice Mutation Nature Neuraxis Newborn Infant Osteoblasts Osteoclasts Osteogenesis Osteopenia Osteoporosis Patients Phenotype Physiology Receptor Signaling Regulation Relative (related person)Series Serotonin Serotonin Production Serum Signal Transduction Skeleton Testing Tryptophan 5-monooxygenase Vertebrates Wnt proteins autocrine base bone bone loss bone mass fly gain of function mutation inhibitor/antagonist loss of function mutation men overexpression proto-oncogene protein Wnt-2 research study serotonin receptor serotonin transporter skeletal dysplasia transcription factor tumor

项目摘要

Project Summary Lrp5 is a positive regulator of bone formation in vertebrates. It is generally assumed that it fulfills this function as a coreceptor for Wnt proteins. However, disrupting canonical Wnt signaling in osteoblasts does not affect bone formation thus raising the testable hypothesis that Lrp5 uses other and/or additional means to regulate bone formation. While testing this hypothesis we have generated a large body of preliminary data indicating that in absence of Lrp5 there is a severe increase in circulating levels of peripherally produced serotonin, which known to be produced by the enterochromaffin cells of the gut (duodenum). Based on this body of preliminary data we hypothesize that, in mice and men, the bone diseases triggered by loss- or gain-of-function mutations in Lrp5 are endocrine diseases originating from the gut and mediated by serotonin. To demonstrate the validity of our hypothesis we propose to pursue the following specific aims: - To generate and analyze mice lacking Lrp5 in either osteoblasts or duodenum to determine the cellular origin of the bone phenotype caused by Lrp5 inactivation. - To generate and analyze mutant mice lacking Tph1 in osteoblasts or duodenum to determine whether serotonin acts on osteoblast in an autocrine or endocrine manner. - To determine through genetic means whether a gain-of-function mutation in Lrp5 affects bone mass in a serotonin-dependent manner. - To use genetic assays to identify serotonin signaling receptors in osteoblasts - To determine genetically whether CREB is the transcription factor acting downstream of serotonin in osteoblasts.

项目概要 Lrp5 是脊椎动物骨形成的正调节因子。一般认为它满足该功能作为 Wnt 蛋白的辅助受体。然而，破坏经典的 Wnt 信号传导成骨细胞不影响骨形成，因此提出了 Lrp5 使用的可检验假设调节骨形成的其他和/或附加方法。在检验这个假设时，我们有生成了大量初步数据，表明在缺乏 Lrp5 的情况下，存在严重的外周产生的血清素的循环水平增加，已知血清素是由肠道（十二指肠）的肠嗜铬细胞。基于这些初步数据，我们假设，在小鼠和人类中，由功能丧失或获得引起的骨疾病 Lrp5 突变是源自肠道、由血清素介导的内分泌疾病。为了证明我们假设的有效性，我们建议追求以下具体目标： - 生成并分析成骨细胞或十二指肠中缺乏 Lrp5 的小鼠以确定 Lrp5 失活引起的骨表型的细胞起源。 - 生成并分析成骨细胞或十二指肠中缺乏 Tph1 的突变小鼠以确定血清素是否以自分泌或内分泌方式作用于成骨细胞。 - 通过遗传手段确定 Lrp5 的功能获得性突变是否会影响骨量以血清素依赖性方式增加。 - 使用基因检测来识别成骨细胞中的血清素信号受体 - 从遗传学上确定 CREB 是否是作用于下游的转录因子成骨细胞中的血清素。