Grant: Discovery Grants Program - Individual

Our lab identified a protein, called Numb Interacting Protein 1 (NIP1), that has been shown to be essential for the function of dual oxidase 1 (DUOX1) and the production of reactive oxygen species (ROS) (Grasberger & Refetoff, 2006). Studies into the role of NIP1 revolve primarily around its association with DUOX1 in the thyroid, where it is responsible for ROS and thyroid hormone production, and in the lung, where it has recently been shown to be important for host defence. However, our lab has discovered that NIP1 is widely expressed in the developing mouse embryo, and we have demonstrated that its over-expression in mouse carcinoma embryonal P19 cells increases ROS levels, and promotes neurogenesis (Kennedy et al., 2010) in the absence of the common chemical inducer, retinoic acid. In spite of proven links to ROS production, hormone biosynthesis and host defence, and potential links to differentiation and development, detailed studies into roles for NIP1 during neuronal development and repair have not been considered. Given its expression levels in the developing embryo, and the effects of its manipulation on P19 cells, we hypothesize that NIP1 is an important regulator of mouse and human embryonic stem cell differentiation. In order to test this hypothesis, we plan to use mouse embryonic stem (mES) and human embryonic stem (hES) cells to support findings in P19 cells. We plan to characterize NIP1 expression in pluripotent and differentiating mES and hES cell cultures, and subsequently manipulate its levels to determine the effects of NIP1 overexpression and knockdown on neurogenesis. We hypothesize that, similar to results from P19 cells, that NIP1 overexpression will enhance mES cell differentiation into neurons. Due to our previous findings that NIP1 is an intrinsic neuronal cell fate determinant in stem cell differentiation, we believe it represents a potential useful target for developing stem cell-based therapeutic strategies for the treatment of neurodevelopmental disorders and neurodegenerative diseases.