Pre Clinical Discovery Core

摘要 临床前研究对于靶点识别和验证、机制测试是必要的。 假说，以及在适当的临床前动物模型中进行的初步概念验证研究，并代表 将功能促进疗法(FPTs)推向人体试验的必要前提。一个重要的方面 在模式生物中进行翻译研究的基本观点是，生理过程 在动物模型中评估的结果与在人类身上观察到的情况非常相似，从而允许剂量和 效果外推。此外，为了对临床前研究的结果进行有意义的解释， 测量必须是可重复性的、准确的，并与在人体上观察到的条件足够相似。 因此，波士顿OAIC已经建立了临床前发现核心，该核心提供标准化 用于肌肉表现和身体功能分析的程序和最先进的设备， 肌肉生物能量学、非侵入性成像和全身代谢结果。PDC提供 评估身体成分(瘦体重、整体体重)的标准化、最先进的方法和仪器 身体和局部脂肪质量，骨骼肌质量，使用高分辨率的肌肉功能显微镜 磁共振成像)在衰老和疾病的动物模型中用于量化对 功能促进疗法。PDC还为早期职业调查人员提供咨询服务，以 优化研究设计，指导选择合适的实验模型和结果措施。 PDC已为其相关工作人员的培训和认证建立了标准化程序， 在其程序中保持严格的质量控制。标准作业程序已通过 参与机构的IACUC，以简化参与机构的动物转移 实验室到PDC设施。PDC继续创新并提供新的测量模式，以 促进FPT发现。PDC领导层与设备制造商密切合作，不断 改进方法并提高时间分辨率(信噪比)、精度和灵敏度 它提供的技术。拟议的开发项目将应用超高场7特斯拉磁铁 非侵入性测定骨骼NAD/NADH的磁共振波谱方法 肌肉和大脑能够在体内评估线粒体的效率，而不需要组织活检。 PDC已成为OAIC资助的REC和PESC项目以及外部资助项目的独特资源 使用临床前模型进行FPT发现研究的OAIC项目。PDC资助的研究有 促进了几次成功的NIH拨款提交和OAIC调查人员的同行审查出版物。

Summary The preclinical studies are necessary for target identification and validation, for testing mechanistic hypotheses, and for initial proof-of-concept studies in appropriate pre-clinical animal models and represent an essential pre-requisite for advancing function promoting therapies (FPTs) to human trials. An important aspect of translational research in model organisms is the underlying assertion that the physiological processes that are evaluated in animal models are sufficiently similar to conditions observed in humans to allow dose and effect extrapolation. Additionally, for the outcomes of preclinical studies to be meaningfully interpreted, measurements must be reproducible, accurate, and sufficiently similar to the conditions observed in humans. Accordingly, the Boston OAIC has established a Preclinical Discovery Core that offers standardized procedures and state-of-the-art equipment for the analysis of muscle performance and physical function, muscle bioenergetics, and non-invasive imaging and whole body metabolic outcomes. The PDC provides standardized, state-of-the-art methods and instruments to assess body composition (lean body mass, whole body and regional fat mass, skeletal muscle mass, functional microscopy of the muscle using high resolution magnetic resonance imaging) in animal models of aging and disease to quantify outcomes in response to function promoting therapies. The PDC also offers consultative services to early career investigators to optimize study design, and guide the selection of appropriate experimental model and outcome measures. The PDC has established standardized procedures for training and certification of its staff involved, and for maintaining strict quality control in its procedures. The standard operating procedures have been approved by the IACUCs of the participating institutions to enable streamlined transfer of animals from the participating laboratory to the PDC facility. The PDC continues to innovate and provide novel measurement modalities to facilitate FPT discovery. The PDC leadership has worked closely with equipment manufacturers to continually refine the methods and improve the temporal resolution (signal to noise ratio), precision, and sensitivity of the techniques that it offers. The proposed developmental project will apply an ultra-high-field 7-tesla Magnetic Resonance Spectroscopy (MRS) method for the non-invasive measurement of NAD+/NADH in the skeletal muscle and brain enabling an in vivo assessment of mitochondrial efficiency without a tissue biopsy. The PDC has become a unique resource for OAIC-funded REC and PESC projects, and for externally-funded OAIC projects that are using preclinical models for FPT discovery research. The PDC supported studies have facilitated several successful NIH grant submissions and peer reviewed publications by OAIC investigators.