Pre Clinical Discovery Core

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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.