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.

项目摘要 LRP5是脊椎动物骨形成的正调节剂。通常认为它可以实现该功能是Wnt蛋白的共核能。但是，破坏规范的Wnt信号传导成骨细胞不影响骨形成，从而提出了LRP5使用的可检验的假设其他和/或其他调节骨形成的方法。在检验此假设时，我们有产生了大量的初步数据，表明在没有LRP5的情况下，有一个严重的周围产生的5-羟色胺的循环水平增加，已知由肠道的肠球菌细胞（十二指肠）。基于这一初步数据我们假设在小鼠和男性中，骨骼疾病是由损失或功能获得的触发的 LRP5中的突变是源自肠道并由5-羟色胺介导的内分泌疾病。为了证明我们的假设的有效性，我们建议追求以下特定目的： - 生成和分析成骨细胞或十二指肠缺乏LRP5的小鼠以确定由LRP5失活引起的骨表型的细胞起源。 - 生成和分析在成骨细胞或十二指肠中缺少TPH1的突变小鼠以确定 5-羟色胺是否以自分泌方式或内分泌方式对成骨细胞作用。 - 通过遗传确定LRP5中功能障碍突变是否影响以5-羟色胺依赖性方式进行骨骼质量。 - 使用遗传测定识别成骨细胞中的5-羟色胺信号受体 - 从遗传上确定CREB是否是在下游的转录因子成骨细胞中的5-羟色胺。