MOLECULAR AND GENETIC DISSECTION OF SEROTONIN REGULATION OF BONE MASS

血清素对骨量调节的分子和基因剖析

• 批准号: 7772521
• 负责人: Vijay K Yadav
• 金额: $ 9万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-04 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7772521
• 关键词: Address; Affect; Aging; Arm Bones; Attention; Blood; Bone Resorption; Bone remodeling; Brain; Cells; Classification; Consultations; Data; Disease; Dissection; Duodenum; Endocrine; Enterochromaffin Cells; Enzymes; Failure; General Population; Genes; Genetic; Goals; Hand; Hormones; Human; In Situ; Incidence; Infant; Knowledge; Maintenance; Mediating; Melatonin; Mentors; Mentorship; Molecular; Molecular Genetics; Mothers; Mus; Mutation; Neurosecretory Systems; Neurotransmitters; Osteoblasts; Osteogenesis; Osteoporosis; Pathogenesis; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Positioning Attribute; Postmenopausal Osteoporosis; Pregnancy; Proteins; Regulation; Relative (related person); Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Serotonin Production; Therapeutic; Time; Tryptophan 5-monooxygenase; Work; abstracting; bone; bone loss; bone mass; design; gain of function mutation; genetic analysis; improved; in vivo; inhibitor/antagonist; insight; novel; novel therapeutics; postnatal; prenatal; prevent; programs; public health relevance; receptor; skeletal dysplasia; skeletogenesis; tool

DESCRIPTION (provided by applicant): PROJECT ABSTRACT The overall goal of this K99/R00 Application is to improve our understanding of the genetic and molecular control of bone remodeling by identifying a novel regulator, elucidating its modes of action and documenting its therapeutic importance. This application will examine (1) the role of brain-derived serotonin in the regulation of bone formation and its mechanisms of action; (2) the functional hierarchy between brain-derived and gut-derived serotonin; (3) the therapeutic potential of inhibiting the synthesis of gut-derived serotonin; (4/5) the implications of alterations in the serotonin levels through synthetic serotonin reuptake inhibitors (SSRIs) during pre- and postnatal period in skeletogenesis and acquisition of bone mass accrual, and (6) and the role of melatonin in the regulation of bone remodeling. The first three aims of this project will be done under the mentorship of Dr. Gerard Karsenty while the last three aims will be done in the independent phase of this application. The coordination of these projects and a smooth transition from K99 to R00 phase of this application will be performed by the program director in consultation with Dr. Gerard Karsenty. This will be facilitated, due to the synergy and at the same time diversity between the K99 and R00 parts of this application, by continuous interactions. Together, these studies should provide important and novel insights into the genetic and molecular control of bone remodeling as well as in the pathogenesis and treatment of osteoporosis, a major disease of aging. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Serotonin is a hormone/ neurotransmitter that has attracted a tremendous amount of attention because of its ability to regulate several neuroendocrine/ endocrine functions. In the context of the recent demonstration of an endocrine pathway regulating bone remodeling through gut-derived serotonin, it is important to understand the effect of brain-derived serotonin in the regulation of bone mass. This is a critically important question if one wants to use this pathway to design novel anabolic drugs for treatment of osteoporosis. This project will explore genetically and in vivo, the therapeutic implications of gut-derived serotonin and whether brain-derived serotonin and its metabolite melatonin regulate bone mass.

描述（由申请人提供）： 项目摘要 该 K99/R00 应用的总体目标是通过识别新型调节剂、阐明其作用模式并记录其治疗重要性，提高我们对骨重塑的遗传和分子控制的理解。该应用将检查（1）脑源性血清素在骨形成调节中的作用及其作用机制； (2) 脑源性和肠道源性血清素之间的功能层次； (3) 抑制肠源性血清素合成的治疗潜力； (4/5) 产前和产后期间通过合成血清素再摄取抑制剂 (SSRI) 改变血清素水平对骨骼形成和骨量增长的影响，以及 (6) 以及褪黑素在骨调节中的作用重塑。该项目的前三个目标将在 Gerard Karsenty 博士的指导下完成，而后三个目标将在该应用程序的独立阶段完成。这些项目的协调以及该应用程序从 K99 到 R00 阶段的平稳过渡将由项目主任与 Gerard Karsenty 博士协商进行。由于该应用程序的 K99 和 R00 部分之间的协同作用和同时的多样性，通过持续的交互将促进这一点。总之，这些研究应该为骨重塑的遗传和分子控制以及骨质疏松症（一种主要的衰老疾病）的发病机制和治疗提供重要而新颖的见解。 公共卫生相关性： 项目叙述 血清素是一种激素/神经递质，由于其调节多种神经内分泌/内分泌功能的能力而引起了极大的关注。在最近证明内分泌途径通过肠源性血清素调节骨重塑的背景下，了解脑源性血清素在骨量调节中的作用非常重要。如果人们想利用这一途径来设计用于治疗骨质疏松症的新型合成代谢药物，这是一个至关重要的问题。该项目将从遗传和体内角度探索肠道来源的血清素的治疗意义，以及脑源性血清素及其代谢物褪黑激素是否调节骨量。

项目成果

Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis.

• DOI: 10.1038/nm.2098
• 发表时间: 2010-03
• 期刊: NATURE MEDICINE
• 影响因子: 82.9
• 作者: Yadav, Vijay K.;Balaji, Santhanam;Suresh, Padmanaban S.;Liu, X. Sherry;Lu, Xin;Li, Zhishan;Guo, X. Edward;Mann, J. John;Balapure, Anil K.;Gershon, Michael D.;Medhamurthy, Rudraiah;Vidal, Marc;Karsenty, Gerard;Ducy, Patricia
• 通讯作者: Ducy, Patricia

Leptin-dependent co-regulation of bone and energy metabolism.

• DOI: 10.18632/aging.100100
• 发表时间: 2009-11-05
• 期刊: Aging
• 作者: Yadav VK;Karsenty G
• 通讯作者: Karsenty G