Determining the Role of Plastin-3 in Osteoblast Differentiation and Mineralization

确定 Plastin-3 在成骨细胞分化和矿化中的作用

基本信息

批准号：
10313727
负责人：
Samantha Meagan Chin
金额：
$ 3.2万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10313727
关键词：
2 year old Actins Address Adult Affect Alkaline Phosphatase Biochemical Biological Models Biology Bone Density Bone Development Bone Diseases Bone Resorption Bundling Calcium Cellular biology Child Childhood Clinical Collagen Diseases Core Facility Cytoskeleton Defect Development Diagnosis Disease Elderly F-Actin Fishes Fracture Functional disorder Future Genes Genetic study Goals In Vitro Individual Institution Knock-in Life Light Link Mediating Medical Mentorship Modeling Molecular Mus Musculoskeletal Mutation Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteoporosis Osteoporotic Pathogenicity Pathway interactions Patients Physicians Physiologic calcification Physiological Play Process Proteins Recording of previous events Recurrence Regulation Research Research Personnel Role Scientist Structure Techniques Testing Therapeutic Time Training Training Programs Transgenic Organisms Undifferentiated Universities Washington Zebrafish age related bone bone fragility bone health bone loss bone mass bone turnover early onset effective therapy experimental study genetic analysis in vivo in vivo Model insight knock-down mineralization multidisciplinary mutant new therapeutic target novel osteoblast differentiation osteogenic plastin response side effect skills therapeutic target transcriptome sequencing treatment response

项目摘要

Samantha Chin (PD/PI) PROJECT SUMMARY/ABSTRACT Osteoporosis is the most common bone disorder in the world and represents a significant clinical and societal burden due to related bone fractures. Although classically viewed as an age-related disorder, osteoporosis now more commonly describes a general condition of low bone mineral density that can arise in children as well as adults. The mainstay of osteoporosis treatment is anti-resorptive therapy, which seeks to curb bone resorption. This approach, however, is plagued by undesirable side-effects and concerns regarding long- term efficacy, particularly in children, underscoring the pressing need for alternative therapeutic targets and strategies to effectively treat osteoporosis. Plastin-3 (PLS3) is a calcium-sensitive actin-bundling protein that has recently been linked to the development of childhood-onset osteoporosis; however, the underlying pathophysiology is completely unknown. This is due in part to the fact that the role of PLS3 in bone health remains to be identified. This proposal will address these questions and build a basis to develop PLS3 as a novel anabolic anti-osteoporosis target. Genetic studies in mouse and zebrafish models suggest that PLS3 plays a role in osteoblast-mediated bone formation; however, it remains unclear how PLS3 mechanistically contributes to these processes. Aim 1 will employ pathogenic PLS3 mutants that are defective in either actin-bundling or calcium-regulation to elucidate how PLS3 promotes osteoblast differentiation and mineralization in cultured osteoblasts. In addition, RNA-seq analysis will also be used to identify novel pathways that contribute to mineralization in order to provide insight to the specific role of PLS3 and actin dynamics in osteoblast mineralization. To better understand how PLS3 contributes to regulation of bone development in vivo, Aim 2 is focused on developing a zebrafish model system to study the effect of pathogenic PLS3 mutations on bone formation. Taken together, this proposal will fill major gaps in our understanding of how PLS3 and its regulation of actin cytoskeleton dynamics contribute to bone health and the development of osteoporosis. The applicant has assembled a multi-disciplinary mentorship team with experts in the actin cytoskeleton, bone biology, cell biology, and zebrafish model systems that will support the applicant in completion of these aims. The proposal also takes advantage of the Washington University’s strengths in musculoskeletal and zebrafish research including the institution’s cutting-edge cores and facilities. Additionally, Washington University Medical Scientist Training Program has a rich history of supporting physician scientists at various stages of training that will also be invaluable to the applicant’s development. This training and mentorship will provide the applicant critical skills that will facilitate the transition to independent researcher and physician-scientist.

萨曼莎·钦 (PD/PI) 项目概要/摘要骨质疏松症是世界上最常见的骨病，代表着重要的临床和健康问题。相关骨折造成的社会负担虽然传统上被视为与年龄相关的疾病，骨质疏松症现在更常见地描述了骨矿物质密度低的一般情况，可能出现在儿童和成人骨质疏松症治疗的主要方法是抗骨吸收治疗，旨在遏制骨质疏松症。然而，这种方法受到不良副作用和对长期骨吸收的担忧的困扰。长期疗效，特别是在儿童中，强调迫切需要替代治疗目标和有效治疗骨质疏松症的策略 Plastin-3 (PLS3) 是一种钙敏感肌动蛋白捆绑蛋白，具有最近发现与儿童期发病的骨质疏松症的发生有关；然而，其根本原因是病理生理学完全未知，部分原因是 PLS3 在骨骼健康中的作用。该提案将解决这些问题并为开发 PLS3 奠定基础。合成代谢抗骨质疏松症目标。小鼠和斑马鱼模型的遗传学研究表明 PLS3 在成骨细胞介导的骨中发挥作用然而，目前还不清楚 PLS3 如何机械地促进这些过程。利用肌动蛋白成束或钙调节有缺陷的致病性 PLS3 突变体来阐明 PLS3 如何促进培养的成骨细胞中的成骨细胞分化和矿化此外，RNA-seq。分析还将用于确定有助于矿化的新途径，以便提供见解 PLS3 和肌动蛋白动力学在成骨细胞矿化中的具体作用更好地了解 PLS3 如何发挥作用。有助于体内骨骼发育的调节，目标2专注于开发斑马鱼模型系统研究致病性 PLS3 突变对骨形成的影响综上所述，该提案将填补重大空白。我们对 PLS3 及其对肌动蛋白细胞骨架动力学如何影响骨骼的理解存在差距健康和骨质疏松症的发展。申请人组建了一个由肌动蛋白细胞骨架专家组成的多学科指导团队，骨生物学、细胞生物学和斑马鱼模型系统将支持申请人完成这些该提案还利用了华盛顿大学在肌肉骨骼和健康方面的优势。斑马鱼研究，包括该机构的尖端核心和设施，此外，华盛顿大学。医学科学家培训计划在支持不同阶段的医学科学家方面有着丰富的历史对申请人的发展也非常有价值的培训和指导将提供申请人的关键技能将有助于向独立研究员和医师科学家的过渡。