A chemical-genetic model for pharmacological mTOR studies across tissues and organs

About This Grant

PROJECT SUMMARY/ABSTRACT The mammalian target of rapamycin (mTOR) is an essential regulator of cell growth, proliferation, and metabolism, with implications in diseases like cancer, neurodegeneration, cardiovascular diseases, and metabolic disorders. While systemic mTOR inhibition via rapamycin has therapeutic potential, it often leads to side effects necessitating targeted mTOR modulation to maximize benefits while minimizing adverse effects. This R21 grant application aims to develop a precise, pharmacological approach to modulating mTOR signaling for a thorough understanding of its role in health and disease. The ubiquitous expression of mTOR complicates targeted inhibition with rapamycin due to its systemic effects. We propose creating a novel chemical-genetic animal model for programmable mTOR modulation, tailored to human health and diseases affecting multiple body systems. Specific Aim 1 focuses on developing this model using a rapamycin analog (rapalog) that inhibits mTOR only upon binding to a mutant FKBP12 protein. This will involve conditional, tissue-specific expression of a mutant FKBP12, enabling precise pharmacological mTOR activity control in selected tissues or organs. Specific Aim 2 uses this model to assess the cell-autonomous and non-cell-autonomous effects of skeletal muscle-specific, pharmacological mTOR modulation across multiple tissues, organs, and body systems. We will activate mutant FKBP12 expression in skeletal muscle and examine the cell-autonomous and non-cell- autonomous effects on various tissues and organs across body systems through comprehensive phenotypic characterization, including histological, molecular, and physiological assessments. We aim to identify key mediators altered by muscle-specific mTOR inhibition that impact other organ systems and clarify cell- autonomous effects of pharmacological mTOR inhibition in skeletal muscle. Developing and validating this inducible, tissue-specific model will enhance the rigor of mTOR studies across different body systems. The model and materials will be made available to the research community. This research holds broad relevance for multiple NIH Institutes and Centers by enabling detailed pharmacological studies of mTOR across various body systems and diseases. The insights enabled by our model will be crucial for understanding and treating conditions such as, but not limited to, metabolic disorders, endocrine dysfunctions, immune diseases, neurodevelopmental, and neurodegenerative conditions, aligning with the NIH’s mission to advance biomedical research and scientific progress.