权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Structural, Molecular and Functional Specialization in Osteocyte Mechanosensing

骨细胞机械传感的结构、分子和功能专业化

基本信息

批准号：
10394277
负责人：
MITCHELL B SCHAFFLER
金额：
$ 62.82万
依托单位：
CITY COLLEGE OF NEW YORK
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-11 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10394277
关键词：
Acute Affect Affinity Androgens Binding Biochemical Bone Diseases Bone Resorption Bone remodeling Calcium Cell Signaling Process Cell physiology Cells Co-Immunoprecipitations Complex Data Effector Cell Elements Endocrine Estrogens Fingers Fluorescence Resonance Energy Transfer Focal Adhesions Frequencies Funding Genes Genetic Models Goals Gonadal Steroid Hormones Hormonal Hormonal Change Hormones Image In Vitro Individual Integrin alphaVbeta3 Integrins Intervention Ion Channel Life Mechanical Stimulation Mechanics Membrane Methods Microscopy Modeling Molecular Mus Mutation Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteoporosis prevention P2X-receptor Pathway interactions Pattern Pharmacology Physiological Process Property Purinoceptor Reporter Reporting Resolution Role Series Signal Pathway Signal Transduction Site Skeleton Structure Surface Plasmon Resonance System T-Type Calcium Channels Techniques Testing United States National Institutes of Health base beta catenin bone bone cell bone fragility bone health experimental study follow-up imaging modality imaging system improved in vivo individual response innovation mechanical load mechanical signal mechanical stimulus mechanotransduction molecular assembly/self assembly mouse genetics multidisciplinary new therapeutic target novel receptor recruit response restoration sensor

项目摘要

ABSTRACT Bone adapts its structure to mechanical loading. This adaption is essential for growing the right skeleton and maintaining its integrity throughout life. Osteocytes are the cells responsible for sensing and coordinating response to mechanical load. Key recent discoveries reported by our group during the last several years established that osteocyte cell processes function as unique mechanosensory elements. Processes are >10-fold more sensitive to mechanical stimuli than osteocyte cell bodies. Moreover, this triggering of Ca2+ signaling from cell processes occurs through a unique complex of aVb3 integrins, membrane channels and receptors, that occur at attachment points to the canalicular walls, and which we call the “Osteocyte mechanosome.” This proposal is based on the global hypothesis that a novel structure localized on osteocyte processes, the osteocyte mechanosome, detects and transduces mechanical signals. To date, we have identified four key osteocyte mechanosome components: αVβ3 integrin, pannexin1, P2X7 receptor (P2X7R) and the CaV3.2 T-type calcium channel. Our multidisciplinary team will test this hypothesis by multiple approaches in each of three aims. In Aim 1 we will combine biochemical techniques (co-immunoprecipitation, surface plasmon resonance) and imaging modalities (FRAP, FRET and STORM super-resolution microscopy) to define comprehensively the structural and dynamic properties of this heretofore unknown transduction complex, the osteocyte mechanosome in osteocytic cells in vitro. In Aim 2 we test how pharmacological and genetic alteration of individual mechanosome components alters upstream (Ca2+) and downstream (to bone) signaling in osteocytic cells in vitro. In Aim 3, we will combine our novel OtGP3 osteocyte Ca2+ reporter mice-in vivo loading/imaging system with pharmacological manipulations to confirm effects of key mechanosome components (as identified in Aims 1 and 2) on osteocyte Ca2+ response and on downstream signaling. We will also use this approach to answer the fundamental question of whether osteocyte Ca2+ responses to mechanical loading altered by loss of constitutive sex hormones (estrogen/androgen) or by anabolic PTH.

摘要骨使其结构适应机械负荷。这种适应对于发展正确的骨骼和维持其完整性贯穿一生。骨细胞是负责感测和协调对机械负载的响应。我们最近报告的关键发现在过去的几年里，一个小组确定骨细胞的细胞过程功能是独特的，机械感觉元件过程对机械刺激的敏感度是骨细胞胞体此外，这种从细胞过程触发Ca 2+信号传导的情况发生在通过aVb 3整联蛋白、膜通道和受体的独特复合物，发生在附着点在小管壁上，我们称之为“骨细胞机械体”。这一建议是基于一个全球性的假设，即一个新的结构定位于骨细胞骨细胞机械体处理、检测和传递机械信号。到目前为止，我们已经鉴定了四种关键的骨细胞机械体成分：αVβ3整联蛋白，泛连接蛋白1， P2 X7受体（P2 X7 R）和CaV3.2 T型钙通道。我们的多学科团队将通过三个目标中的每一个目标的多种方法来测试这个假设。在目标1中，我们将联合收割机生物化学技术（免疫共沉淀，表面等离子体共振）和成像模式（FRAP，FRET和STORM超分辨率显微镜），以全面定义这种迄今未知的转导复合物的结构和动力学性质，体外骨细胞中的骨细胞机械小体。在目标2中，我们测试了药理学和单个机械体组分的遗传改变改变上游（Ca 2+），体外骨细胞中的下游（至骨）信号传导。在目标3中，我们将联合收割机 OtGP 3骨细胞Ca 2+报告基因小鼠体内载药/成像系统操作，以确认关键机械体组分的作用（如目的1和 2)对骨细胞Ca 2+反应和下游信号传导的影响。我们还将使用这种方法来回答了骨细胞钙离子是否对机械负荷有反应的基本问题因组成性性激素（雌激素/雄激素）丢失或合成代谢PTH而改变。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Estrogen depletion on In vivo osteocyte calcium signaling responses to mechanical loading.

DOI：
10.1016/j.bone.2021.116072
发表时间：
2021-11
期刊：
Bone
影响因子：
4.1
作者：
Lewis KJ;Cabahug-Zuckerman P;Boorman-Padgett JF;Basta-Pljakic J;Louie J;Stephen S;Spray DC;Thi MM;Seref-Ferlengez Z;Majeska RJ;Weinbaum S;Schaffler MB
通讯作者：
Schaffler MB

A Bisphosphonate With a Low Hydroxyapatite Binding Affinity Prevents Bone Loss in Mice After Ovariectomy and Reverses Rapidly With Treatment Cessation.

DOI：
10.1002/jbm4.10476
发表时间：
2021-04
期刊：
JBMR plus
影响因子：
3.8
作者：
Coffman AA;Basta-Pljakic J;Guerra RM;Ebetino FH;Lundy MW;Majeska RJ;Schaffler MB
通讯作者：
Schaffler MB

Role of pannexin 1 channels in load-induced skeletal response.

pannexin 1 通道在负荷诱导的骨骼反应中的作用。

DOI：
10.1111/nyas.13914
发表时间：
2019
期刊：
Annals of the New York Academy of Sciences
影响因子：
5.2
作者：
Seref-Ferlengez,Zeynep;Urban-Maldonado,Marcia;Sun,HuiB;Schaffler,MitchellB;Suadicani,SylviaO;Thi,MiaM
通讯作者：
Thi,MiaM

Induction of somatopause in adult mice compromises bone morphology and exacerbates bone loss during aging.

DOI：
10.1111/acel.13505
发表时间：
2021-12
期刊：
Aging cell
影响因子：
7.8
作者：
Dixit M;Duran-Ortiz S;Yildirim G;Poudel SB;Louis LD;Bartke A;Schaffler MB;Kopchick JJ;Yakar S
通讯作者：
Yakar S

A multiscale fluidic device for the study of dendrite-mediated cell to cell communication.