Center of Biomedical Research Excellence in Matrix Biology Phase II

基质生物学卓越生物医学研究中心第二期

基本信息

批准号：
10844074
负责人：
JULIA THOM OXFORD
金额：
$ 72.34万
依托单位：
BOISE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10844074
关键词：
3-Dimensional Acceleration Actins Address Aging Anabolism Area Atomic Force Microscopy Attenuated Award Basic Science Bed rest Behavioral Research Biological Biology Biomechanics Biomedical Research Biophysics Bioreactors Cell Nucleus Cell Proliferation Cell physiology Cells Cellular Structures Centers of Research Excellence Clinic Clinical Clinical Research Collaborations Collagen Complex Cytoskeleton DNA Development Disabled Persons Disease Disease Progression Elements Engineering Exclusion Exercise Extracellular Matrix Extracellular Matrix Proteins F-Actin Focal Adhesions Frequencies Gene Expression Geometry Goals Grant Health Human Image In Vitro Injury Interdisciplinary Study Intervention Knowledge Lead Machine Learning Measurement Measures Mechanics Mediating Mesenchymal Stem Cells Methods Microgravity Microscope Modality Modeling Morphology Motion Muscle Musculoskeletal Nuclear Nuclear Envelope Nuclear Import Nuclear Protein Osteocytes Osteolytic Osteoporosis Outcome Parents Pathology Periodicity Phase Population Prevention Production Proteins Rejuvenation Reporting Research Research Personnel Research Training Role Science Signal Transduction Signaling Protein Speed Stromal Cells Structure-Activity Relationship Technology Testing Time Tissue Engineering Transcription Coactivator Translational Research Work bone bone cell bone loss bone marrow mesenchymal stem cell cancer cell cell fixing cell growth connective tissue growth factor data pipeline effective therapy enhanced green fluorescent protein improved in silico in vivo lipid biosynthesis live cell microscopy machine learning algorithm mechanical force mechanical signal mechanotransduction multidisciplinary novel novel strategies prevent programs protein expression regenerative response scaffold tissue regeneration tissue repair training opportunity translational study usability vibration

项目摘要

1. PROJECT SUMMARY - Role of Cellular Mechanotransduction of Low Intensity Vibrations in Regulating Extracellular Matrix Synthesis 1.1. Summarize the goal of the parent award: The long-term goal of the Center of Biomedical Research Excellence (COBRE) in Matrix Biology is to establish, enhance, and actively advance a multidisciplinary research center focusing on improving our understanding of the role of the extracellular matrix in development, health, and disease, and contributing to the prevention, treatment, and cure for diseases of high priority. The specific aims of the COBRE Matrix Biology Parent award are: 1) enhance and grow upon the critical mass of investigators established around the thematic multidisciplinary focus of matrix biology, 2) enhance biomedical research core capabilities, 3) grow research collaborations with existing programs, and 4) enhance research training opportunities. This project will supplement the existing COBRE Matrix Biology award to form a new team of investigators that bring together three investigators from IDeA states with different perspectives and expertise to address complex basic, behavioral, clinical and/or translational research questions with complementary approaches. The research question does not duplicate those currently being pursued by the parent award and clearly benefits from the collective efforts of the collaboration. 1.2 Research question to be addressed by the supplement award: Engineering biophysical signals promises non-pharmacologic interventions to direct tissue regeneration in conditions that devastate bone such as osteoporosis, aging, injury, bedrest, or microgravity. Externally applied Low-Intensity Vibrations (LIV), a mechanical signal similar to muscle activity, offers a readily usable technology to stimulate Mesenchymal Stem Cell (MSC) anabolism for both tissue engineering and clinical approaches. LIV does not generate significant matrix deformations in vivo, thus excluding most mechano-transduction mechanisms previously proposed for high-magnitude and low-frequency mechanical signals (e.g., exercise). This presents a significant gap knowledge about bone mechanobiology and prevents utilization of LIV as an effective treatment for bone loss. MSC’s ability to replace and rejuvenate bone cell populations are informed by both dynamic mechanical forces generated during daily activities (e.g. muscle activity) and by the quality of the Extracellular Matrix (ECM). Yes1 Associated Protein (YAP) is a transcriptional co-activator that can activate the expression of genes in response to mechanical force, including ECM molecules such as Connective Tissue Growth Factor (CTGF) to regulate collagen production in cells. For tissue engineering and clinical approaches to ultimately succeed, causative information on how high-frequency signals generated by LIV are sensed, transduced, and eventually lead to nuclear YAP expression and ECM production is critical. This proposal aims to address a fundamental gap in bone mechanobiology by mechanistically establishing a mechanosensory function of the cell nucleus to respond to dynamic accelerations produced by LIV. Using our novel team approach, we will test whether LIV generates relative motions of the nucleus within a cell to strengthen nucleo-cytoskeletal scaffolding and to increase force-induced YAP signaling in the cell nuclei to elicit ECM production. We will address this through three sub-hypotheses and specific aims. The aims of this study are to determine in live cells if 1) vibration frequency and acceleration modulate the LIV- induced nuclear motions and resulting F-actin remodeling, 2) LIV-induced perinuclear F-actin remodeling will increase cytoskeletal tension on the nucleus, 3) the magnitude of cytoskeletal tension on the nucleus determines the magnitude of YAP nuclear entry and ECM production. Completion of these aims will provide knowledge on (1) how to enhance the efficacy of LIV-based regenerative modalities in clinic, and (2) foundational structure-function relationships in MSCs. Results will ultimately enable engineering LIV-based approaches that target nucleo-cytoskeletal connectivity with application in many areas including, but not limited to, tissue regeneration, tissue engineering, and aging. 1.3 Benefit of team science effort: This proposed supplement cannot be accomplished by any single investigator and requires an orchestrated effort by three investigators working in different fields: cell mechanobiology, machine learning, and computational biomechanics. Co-Project Lead (CPL) Uzer will work on establishing experimental methods to measure nuclear motion, high-fidelity cell and biological outcomes, ECM production, and nuclear YAP levels. CPL Satici will focus on developing machine learning algorithms to reconstruct 3D nuclear and cytoskeletal geometries in response to LIV in live cells. CPL Fitzpatrick will develop finite element (FE) models to quantify cytoskeletal forces on the nucleus under LIV treatment. Upon successful completion of this work, our team will establish, for the first time, a novel pipeline for data-driven, cell-specific FE models for understanding force-function relationships in cells. This novel method will lead us to new grant submissions to study the role of cell-specific forces in maintaining healthy cell function and ECM composition as well as informing new translational studies that use LIV to attenuate disease progression both in vitro and in vivo.

1. 项目摘要 - 低强度振动的细胞机械转导在调节中的作用细胞外基质合成 1.1. 总结家长奖的目标：生物医学研究中心的长期目标基质生物学卓越（COBRE）是建立、加强和积极推进多学科研究该中心致力于提高我们对细胞外基质在发育、健康、和疾病，并为高度优先的疾病的预防、治疗和治愈做出贡献。 COBRE 矩阵生物学家长奖的目标是：1) 增强和发展关键的研究人员数量围绕基质生物学这一多学科主题重点建立，2）增强生物医学研究核心能力，3）加强与现有项目的研究合作，4）加强研究培训该项目将补充现有的 COBRE 矩阵生物学奖，组建一个新的团队。调查人员汇集了来自 IDeA 州的三名具有不同观点和专业知识的调查人员通过补充解决复杂的基础、行为、临床和/或转化研究问题研究问题与家长奖目前正在研究的问题不重复。明显受益于合作的集体努力。 1.2 奖项补充要解决的研究问题：工程生物物理信号的承诺在破坏骨骼的情况下，通过非药物干预来指导组织再生，例如骨质疏松症、衰老、受伤、卧床休息或微重力（LIV）。类似于肌肉活动的机械信号，提供了一种易于使用的技术来刺激间充质干组织工程和临床方法的细胞 (MSC) 合成代谢不会产生显着的影响。体内基质变形，因此排除了先前提出的大多数机械传导机制高强度和低频机械信号（例如运动）这呈现出显着的差距。骨力学生物学知识，阻碍了 LIV 作为骨质流失的有效治疗方法的利用。 MSC 替换和恢复骨细胞群活力的能力取决于动态机械力是由日常活动（例如肌肉活动）和细胞外基质 (ECM) 的质量产生的。相关蛋白 (YAP) 是一种转录共激活因子，可以激活响应基因的表达机械力，包括 ECM 分子，如结缔组织生长因子 (CTGF) 来调节细胞中胶原蛋白的产生是组织工程和临床方法最终成功的原因。有关 LIV 生成的高频信号如何被感知、转换并最终导致的信息核 YAP 表达和 ECM 产生至关重要。该提案旨在通过机械地建立一个骨力学生物学的基本差距细胞核的机械感觉功能对 LIV 产生的动态加速度做出反应。新颖的团队方法，我们将测试 LIV 是否在细胞内产生相对于细胞核的运动加强核细胞骨架支架并增加细胞核中力诱导的 YAP 信号传导以引发我们将通过三个子假设和具体目标来解决这个问题。本研究的目的是确定在活细胞中是否 1) 振动频率和加速度调节 LIV- 诱导核运动和由此产生的 F-肌动蛋白重塑，2) LIV 诱导的核周 F-肌动蛋白重塑将增加细胞核上的细胞骨架张力，3）细胞核上的细胞骨架张力的大小决定 YAP 核进入和 ECM 生产的规模。完成这些目标将提供以下方面的知识：(1) 如何增强基于 LIV 的再生疗法的功效 (2) MSC 的基本结构-功能关系结果将最终实现。基于 LIV 的工程方法以核细胞骨架连接为目标，并在许多领域得到应用包括但不限于组织再生、组织工程和衰老。 1.3 团队科学努力的好处：本建议的补充不能由任何一个人来完成研究者，需要由在不同领域工作的三名研究者共同努力：细胞机械生物学、机器学习和计算生物力学联合项目负责人 (CPL) Uzer 将担任。致力于建立测量核运动、高保真细胞和生物学结果的实验方法， ECM 生产和核 YAP 级别将专注于开发机器学习算法。 CPL Fitzpatrick 将开发重建 3D 核和细胞骨架几何形状以响应活细胞中的 LIV。有限元 (FE) 模型可量化 LIV 治疗成功后细胞核上的细胞骨架力。完成这项工作后，我们的团队将首次建立数据驱动、细胞特异性有限元的新颖管道这种新方法将为我们带来新的资助。研究细胞特异性力量在健康维持细胞功能和 ECM 组成中的作用的提交并为使用 LIV 来减轻体外和体内疾病进展的新转化研究提供信息。

项目成果

期刊论文数量（33）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Atomic Force Microscopy Cantilever-Based Nanoindentation: Mechanical Property Measurements at the Nanoscale in Air and Fluid.

基于悬臂的原子力显微镜纳米压痕：空气和流体中纳米尺度的机械性能测量。

DOI：
发表时间：
2022-12-02
期刊：
影响因子：
0
作者：
Enrriques, Ashton E;Howard, Sean;Timsina, Raju;Khadka, Nawal K;Hoover, Amber N;Ray, Allison E;Ding, Ling;Onwumelu, Chioma;Nordeng, Stephan;Mainali, Laxman;Uzer, Gunes;Davis, Paul H
通讯作者：
Davis, Paul H

Wear testing of a canine hip resurfacing implant that uses highly cross-linked polyethylene.

使用高度交联聚乙烯的犬髋关节表面置换植入物的磨损测试。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Warburton, Kevin J;Everingham, John B;Helms, Jillian L;Kazanovicz, Andrew J;Hollar, Katherine A;Brourman, Jeff D;Fox, Steven M;Lujan, Trevor J
通讯作者：
Lujan, Trevor J

LARG GEF and ARHGAP18 orchestrate RhoA activity to control mesenchymal stem cell lineage.

LARG GEF 和 ARHGAP18 协调 RhoA 活性来控制间充质干细胞谱系。

DOI：
10.1016/j.bone.2017.12.001
发表时间：
2018-03
期刊：
Bone
影响因子：
4.1
作者：
Thompson WR;Yen SS;Uzer G;Xie Z;Sen B;Styner M;Burridge K;Rubin J
通讯作者：
Rubin J

Low Intensity Vibrations Augment Mesenchymal Stem Cell Proliferation and Differentiation Capacity during in vitro Expansion.

低强度振动增强间充质干细胞在体外扩增过程中的增殖和分化能力。

DOI：
发表时间：
2020
期刊：
影响因子：
4.6
作者：
Bas, Guniz;Loisate, Stacie;Hudon, Stephanie F;Woods, Kali;Hayden, Eric J;Pu, Xinzhu;Beard, Richard;Oxford, Julia T;Uzer, Gunes
通讯作者：
Uzer, Gunes

Influence of Woodsmoke Exposure on Molecular Mechanisms Underlying Alzheimer's Disease: Existing Literature and Gaps in Our Understanding.

木烟暴露对阿尔茨海默病分子机制的影响：现有文献和我们理解的差距。