Lrp5-dependent regulation of bone mass accrual by gut-derived serotonin

肠源性血清素对骨量增长的 Lrp5 依赖性调节

基本信息

批准号：
7817117
负责人：
Gerard Karsenty
金额：
$ 43.78万
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/7817117
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 public health relevance research study serotonin receptor serotonin transporter skeletal dysplasia transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: We have identified Tph1, a gene governing serotonin production in gut cells, as the gene most affected by the absence of Lrp5, a major regulator of osteoblast proliferation and bone formation implicated in two human disorders of the skeleton. This project will test whether serotonin is a major mediator of Lrp5' regulation of bone mass, whether this effect has a gut origin i.e. is of endocrine nature or has an osteoblastic origin, and will identify the receptor(s) for serotonin in osteoblasts as well as the transcription factor mediating its effect in these cells.

描述（由申请人提供）：LRP5是脊椎动物骨形成的正调节剂。通常假定它可以作为Wnt蛋白的共感染者来实现此功能。但是，破坏成骨细胞中的规范Wnt信号不会影响骨形成，从而提出了可检验的假设，即LRP5使用其他和/或其他手段来调节骨形成。在检验这一假设的同时，我们产生了大量的初步数据，表明在没有LRP5的情况下，周围产生的5-羟色胺的循环水平会严重增加，这是由肠道肠球菌细胞产生的（DuodeNum）。基于这一初步数据，我们假设在小鼠和男性中，在LRP5中损失或功能获取突变触发的骨骼疾病是源自肠道并由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乏TPH1的突变小鼠，以确定5-羟色胺是否以自分泌或内分泌方式对成骨细胞作用。 - 通过遗传来确定LRP5中功能收益突变是否以5-羟色胺依赖性方式影响骨骼。 - 使用遗传测定在成骨细胞中鉴定5-羟色胺信号受体 - 从遗传上确定CREB是否是成骨细胞中5-羟色胺下游作用的转录因子。公共卫生相关性：我们已经确定了TPH1是一种肠道细胞中5-羟色胺产生的基因，是受LRP5缺失影响最大的基因，LRP5是成骨细胞增殖和骨形成的主要调节剂，涉及两种骨骼的人类疾病。该项目将测试5-羟色胺是LRP5'调节骨骼质量的主要介体，该作用是否具有肠道起源，即具有内分泌性质或具有成骨细胞的起源，并且会鉴定成骨细胞中5-羟色胺的受体以及介导其在这些细胞中的转录因子的作用。