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

Mechanical regulation of cytoskeleton guides beta-catenin effect on MSC fate

细胞骨架的机械调节引导β-连环蛋白对MSC命运的影响

基本信息

批准号：
9252230
负责人：
Janet E Rubin
金额：
$ 33.44万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9252230
关键词：
AKT inhibition Actins Adhesions Adipocytes Adipose tissue Adult Bone Formation Stimulation Bone Marrow Cell Lineage Cell Nucleus Cells Complex Cytoskeletal Modeling Cytoskeleton Data Exercise F-Actin Fatty acid glycerol esters Focal Adhesions Goals Grant Health Histologic In Vitro Knock-out Knockout Mice Lamins Marrow Measures Mechanics Mesenchymal Stem Cells Methods Mus Nuclear Obesity Osteogenesis Pathway interactions Periodicity Pharmacology Phosphotransferases Physicians Physiological Population Proteins Recruitment Activity Regulation Regulatory Pathway Resistance Role Running Scientist Signal Pathway Signal Transduction Stem cells Stress Fibers Structure Tamoxifen Testing Time Work base beta catenin bone bone cell bone fragility bone health bone strength improved in vivo innovation lipid biosynthesis mechanical force mechanical load mouse model osteogenic osteoprogenitor cell prevent public health relevance response sedentary skeletal synergism trafficking

项目摘要

DESCRIPTION (provided by applicant): Exercise builds skeletal strength by inducing new bone formation, which is accompanied by decreased marrow adipose tissue (MAT). A lack of exercise enhances MSC adipogenesis, and increased MAT has been shown to be associated with bone fragility. Understanding mechanisms by which exercise regulates mdMSC lineage allocation to increase osteogenesis and decrease adipogenesis is thus significant for managing skeletal health in an increasingly sedentary population. We have shown that mechanical activation and nuclear trafficking of ßcatenin prevents adipogenesis and promotes MSC entry into osteoprogenitor lineage. ßcatenin signaling is initiated by recruitment of Fyn kinase to foca adhesions during strain, followed by Fyn activation of the mTORC2->Akt->GSK3ß inhibition cascade leading to increased ßcatenin. ßcatenin effects depend on cellular context: in mdMSC, increased cytoskeletal structure improves osteogenesis and cytoskeletal deficiency promotes adipogenesis. The Fyn/mTORC2 proximal signal also activates RhoA to build complexity and connectivity of the cytoskeleton. We propose that mechanically induced cytoskeletal reorganization promotes nuclear entry of ßcatenin, underwriting its anti-adipogenic, pro-osteogenic effect. Importantly, the role of focal adhesion-based Fyn in initiating ßcatenin and RhoA effectors may be unique to the mdMSC, potentially providing a specific pharmacologic target to enhance MSC response to exercise. To test this, we will delineate the synergistic contributions of Fyn/mTORC2's two downstream effectors, RhoA and ßcatenin, to MSC lineage fate allocation in vitro and in vivo. We will find if RhoA generated cytoskeletal reorganization is necessary or sufficient to alter mdMSC cell fate and define how mechanical load activates RhoA (SA1). In SA2, we ask if activation of ßcatenin can alter cell fate in the face of cytoskeletal deficiency, inquiring whether the cytoskeleton drives nuclear/cytoplasmic partitioning of ßcatenin and considering if the actin-nesprin-LINC-nuclear tether might guide ßcatenin into the nucleus. In SA3, using an innovative method to quantify and localize MAT, combined with measures of bone formation, we will investigate mechanical control of mdMSC lineage in vivo, asking if the Fyn/mTORC2 signaling unique to mdMSC is critical during exercise stimulation of bone formation; for this we will generate a Tamoxifen driven Prx1-Cre knock out of Fyn.