Cancer genomic analyses performed by our team have allowed us to identify frequently mutated genes in Small Cell Lung Cancer (SCLC). Among these genes, MLL2 was found to undergo loss of function mutations suggesting it could act as a tumor suppressor. MLL2 is a histone methyl transferase that transfers a methyl group to a histone on a DNA strand. This process regulates chromatin state and transcription. More specifically, MLL2 methylates the lysine 4 of histone H3 leading to the activation of gene expression. Interestingly, MLL2 was also recently found mutated in squamous cell lung carcinoma, non-Hodgkin lymphoma, medulloblastoma and cell renal carcinoma pointing out that it could be a novel major tumor suppressor. To investigate this hypothesis, both in vivo (mouse models) and in vitro (cell based assays) will be used. The mouse model consists of a conditional, tissue specific inactivation of two prototype tumor suppressors namely p53 and Rb, which are found highly mutated in SCLC. The role of MLL2 will be studied in this mouse model by generating triple mutants (Rb, p53, and MLL2) mice. The survival of control SCLC mice (p53 and Rb inactivated) will be compared to the survival of the triple mutant (MLL2, Rb, and p53) mice. This critical experiment should enlighten us on the functional role of MLL2 during SCLC development. Molecular and histopathological analyses will also be performed. Additionally, in vitro approaches with human and mouse cells will be used to identify and understand the biological processes and pathways regulated by MLL2. Altogether, it should help us decipher the role of MLL2 in SCLC and it might ultimately lead to the identification of novel treatments and/or preventive options for SCLC.

Jaw joint dysfunction resulting in TMJ has been associated with the development of movement disorders. Displacement of the condylar head (long bony process of the mandible) from the 4/7 Gelb position has been frequently documented in these patients. The use of an oral orthotic creates a vertical distraction that realigns the jaw into proper Gelb position resulting in therapeutic effects. With increasing vertical distraction of the orthotics the distance between the articular eminence and the condylar head was shortened and the angular change of the condyle from its origin was increased. This jaw alignment repositioned the condyle to come forward and down away from the posterior glenoid process. This realignment of the jaw has the potential to restore normal muscular control by the releasing of entrapped branches of the trigeminal nerves. The orthotic may also produce a “sensory trick” that restores normal neural firing, producing both transient and long-term therapeutic effects. This research along with continued investigation of neural mechanism may reveal how oral orthotics are able to suppress debilitating movement disorders.