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：
8666222
负责人：
Donald G Phinney
金额：
$ 64.38万
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/8666222
关键词：
Address Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Applications Grants Behavior Biological Biological Assay Biological Process Biology Bone Marrow Cell Therapy Cells Cellular biology Chromosomal Stability Clinical Clinical Treatment Clinical Trials Communities Complex DNA Damage Disease Experimental Animal Model Failure Future Genetic Growth Health Hematopoiesis Human Human Biology In Vitro Inbreeding Infusion procedures Institution Knock-out Knowledge Laboratories Laboratory Animal Models Link MAPK8 gene Mesenchymal Stem Cells Methods Metric Mitogens Modeling Molecular Mouse Strains Outcome Oxidative Stress Oxygen Pathway interactions Patients Population Pre-Clinical Model Proteins Registries Research Personnel Rodent Rodent Model Role Specific qualifier value Stem Cell Research Systems Biology Testing Toxic effect Transgenic Organisms Treatment Efficacy base cell growth cytokine human TWIST1 protein human disease improved in vivo inhibitor/antagonist macrophage meetings novel pre-clinical repository response species difference stem cell biology stem cell population transcription factor 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）：当前正在180多个开放临床试验中评估间充质干细胞（MSC），以治疗各种人类疾病。尽管MSC在临床疗法中的使用越来越多，但基于在体外或实验动物模型中进行的细胞效力研究，许多基于MSC的临床试验未能达到其主要效果和患者结局的主要终点。实际上，缺乏有关MSC种群功能复杂性的知识，指定有助于细胞效力的细胞行为的途径，这些途径中的物种差异代表了开发优化和可预测的临床疗法的主要障碍。为了克服这些局限性，该提案将比较和对比啮齿动物和人类MSC的基本生物学中的物种差异，确定如何在人群中指定影响细胞效能的不同生物学功能，并证明调节基本细胞生物学和基本细胞生物学和的途径之间的功能联系非验证器功能。为了增强临床前动物模型的价值，该实验室还将创建来自不同近交，转基因和敲除小鼠菌株的MSC存储库，并将这些细胞供应更大的科学界。用于产生细胞的方法产生了非降低的非矛盾种群，该种群概括了人类MSC的功能复杂性和行为。因此，它们的使用提供了一种方法，可以使跨实验室和不同实验动物模型之间的生物学和翻译研究标准化，从而增加了啮齿动物模型的价值，以预测临床领域中细胞行为。