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Species-specific and Systems Biology Approach to MSC-based Therapies

基于 MSC 的治疗的物种特异性和系统生物学方法

基本信息

批准号：
9233785
负责人：
Donald G Phinney
金额：
$ 62.1万
依托单位：
SCRIPPS FLORIDA
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：
2014-05-15 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9233785
关键词：
Address Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Applications Grants Behavior Biological Biological Assay Biological Process Biology Bone Marrow Bone Marrow Stem Cell Cell Therapy Cells Cellular biology Chromosomal Stability Clinical Clinical Treatment Clinical Trials Communities Complex DNA Damage Disease model Experimental Animal Model Failure Future Genetic Growth Health Hematopoiesis Human Human Biology In Vitro Inbreeding Infusion procedures Institution Knock-out Knowledge Laboratories Link MAPK8 gene Mesenchymal Stem Cells Methods Mitogens Modeling Molecular Mouse Strains Oxidative Stress Oxygen Pathway interactions Patient-Focused Outcomes Patients Pharmacology Population Pre-Clinical Model Proteins Registries Research Research Personnel Rodent Rodent Model Role Specific qualifier value Systems Biology TP53 gene TWIST1 gene Testing Toxic effect Transgenic Organisms Treatment Efficacy base biological standardization cell growth clinical predictors cytokine human disease immunoregulation improved in vivo inhibitor/antagonist macrophage novel pre-clinical predictive modeling public health relevance repository response species difference translational study

项目摘要

DESCRIPTION (provided by applicant): Mesenchymal stem cells (MSCs) are currently being evaluated in over 180 open clinical trials for the treatment of a variety of human diseases. Despite the growing use of MSCs in clinical therapy, many MSC-based clinical trials have failed to meet their primary endpoint of efficacy and patient outcomes have been poorly predicted based on cell potency studies conducted in vitro or in experimental animal models. Indeed, lack of knowledge regarding the functional complexity of MSC populations, pathways that specify cellular behaviors that contribute to cell potency, and species differences in these pathways represent a major impediment toward developing optimized and predictable clinical therapies. To overcome these limitations, this proposal will compare and contrast species differences in the basic biology of rodent and human MSCs, determine how different biological functions that affect cell potency are specified within populations, and demonstrate a functional link between pathways that regulate basic cell biology and non-progenitor functions. To enhance the value of pre-clinical animal models, this laboratory will also create a repository of MSCs from different inbred, transgenic, and knockout strains of mice and supply these cells to the greater scientific community. Methods used to produce cells yield non-immortalized, non-clonal populations that recapitulate the functional complexity and behavior of human MSCs. Consequently, their use provides a means to standardize biological and translational studies across laboratories and between different experimental animal models, thereby augmenting the value, of rodent models for predicting cellular behaviors in the clinical arena.

描述（由申请人提供）：间充质干细胞（MSCs）目前正在180多个开放的临床试验中进行评估，用于治疗各种人类疾病。尽管MSCs在临床治疗中的应用越来越多，但许多基于MSCs的临床试验未能达到其主要疗效终点，并且基于体外或实验动物模型进行的细胞效力研究对患者结局的预测也很差。事实上，缺乏对间充质干细胞群体的功能复杂性的了解，指明有助于细胞效力的细胞行为的途径，以及这些途径中的物种差异，是开发优化和可预测的临床治疗的主要障碍。为了克服这些限制，本提案将比较和对比啮齿动物和人类间充质干细胞基本生物学的物种差异，确定影响细胞效力的不同生物学功能如何在群体中被指定，并证明调节基本细胞生物学和非祖细胞功能的途径之间的功能联系。为了提高临床前动物模型的价值，该实验室还将从不同的近交系、转基因和敲除小鼠株中创建一个MSCs库，并将这些细胞提供给更大的科学界。用于生产细胞的方法产生非永生化的、非克隆的群体，这些群体概括了人类间充质干细胞的功能复杂性和行为。因此，它们的使用为跨实验室和不同实验动物模型之间的生物学和转化研究标准化提供了一种手段，从而增加了啮齿动物模型在临床领域预测细胞行为的价值。