Role of mTORC1 In The Regulation Of Prostatic Branching Morphogenesis

Johns Hopkins University, Baltimore MD

Investigators

Abstract

DESCRIPTION (provided by applicant): Prostatic morphogenesis is regulated by a complex cascade of signaling events, precisely integrated over time and space. Decades of research have clearly demonstrated that intercellular communication between urogenital sinus mesenchyme and epithelium is critical for the initiation of prostatic development. Now, the major challenge is to elucidate the intracellular signal transduction networks that integrate this paracrine crosstalk between tissue compartments. In this application, we propose to address this important problem by studying how the mTOR (mammalian target of rapamycin) signaling complex may serve a critical role in integrating upstream signals to promote or inhibit prostatic growth, development and differentiation. In published and preliminary data using a combination of pharmacologic and genetic perturbations, we show that endogenous mTORC1 activity actually suppresses prostatic branching. Here, we propose to test whether this inhibitory role of mTORC1 may stem from negative feedback to upstream androgen and fibroblast growth factor signals required for prostatic branching. Then, we will investigate what cellular mechanisms downstream of mTORC1 signaling may account for its effects on prostatic organogenesis. Using a combination of novel transgenic mouse models that have been previously generated in our lab to induce mTORC1 gain- or loss-of-function, paired with long-term time lapse imaging techniques, we are perfectly poised to extend our work on PI3K (phosphoinositide-3-kinase) signaling in prostatic morphogenesis funded by a previous NIDDK K08 award application. This work is of particular relevance because conditions of abnormal prostatic growth in the adult, such as benign prostatic hyperplasia, are undoubtedly regulated by many of the same signaling networks active during embryonic prostate development. If we can understand and manipulate these same pathways, we may discover new treatment paradigms for this important problem of public health.