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K99/R 00申请的总体目标是通过鉴定一种新的调节剂，阐明其作用模式并记录其治疗重要性，提高我们对骨重建的遗传和分子控制的理解。本申请将研究（1）脑源性5-羟色胺在骨形成调节中的作用及其作用机制;（2）脑源性和肠源性5-羟色胺之间的功能层次;（3）抑制肠源性5-羟色胺合成的治疗潜力;（4/5）通过合成5-羟色胺再摄取抑制剂（SSRIs）改变5-羟色胺水平的影响，（6）褪黑素在骨重建中的调节作用。该项目的前三个目标将在Gerard Karsenty博士的指导下完成，而最后三个目标将在本申请的独立阶段完成。这些项目的协调以及本申请从K99阶段到R 00阶段的平稳过渡将由项目负责人与Gerard Karsenty博士协商进行。由于本申请的K99和R 00部分之间的协同作用和多样性，通过持续的相互作用，这将得到促进。总之，这些研究应该提供重要的和新的见解，骨重建的遗传和分子控制，以及在骨质疏松症的发病机制和治疗，一种主要的衰老疾病。 公共卫生相关性： 项目叙述5-羟色胺是一种激素/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。在最近证明的内分泌途径通过肠源性5-羟色胺调节骨重塑的背景下，重要的是要了解脑源性5-羟色胺在骨量调节中的作用。这是一个至关重要的问题，如果一个人想使用这个途径来设计新的合成代谢药物治疗骨质疏松症。本计画将探讨肠源性血清素的基因及活体治疗意义，以及脑源性血清素及其代谢物褪黑激素是否能调节骨量。

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