In broad terms, the Kelleher lab studies the molecular and cellular mechanisms underlying cognition and cognitive disorders. Current research projects are directed toward defining the molecular mechanisms regulating local protein synthesis in neurons and understanding how these translational mechanisms contribute to normal cognition and the establishment and modification of synaptic connectivity in the mammalian brain. Examination of the role of defective translational control in specific neuropsychiatric disorders is a closely related effort. In a complementary line of research, the lab also investigates the molecular and cellular mechanisms responsible for neurodegenerative dementia, with a focus on Alzheimer's disease.
As an Innovation Fund investigator, Kelleher’s lab is collaborating with the lab of Jeannie Lee, M.D., Ph.D. to combine an expertise in genetics and X-chromosome inactivation with that of neuroscience. Female mammals inherit two X chromosomes, one from each parent, while males inherit only one. In order to ensure that males and females have an equal amount of X chromosome gene expression, females silence the genes on one X chromosome in a process known as X chromosome inactivation (XCI). XCI results in the random inactivation of maternal X chromosomes in some cells and paternal X chromosomes in others. Notably, cellular differences are exhibited depending on whether a cell expresses the male- or female-inherited X chromosome. In females with Turner syndrome, cells carry only one copy of the X chromosome, either from the mother or the father. Together, Lee and Kelleher will utilize mouse models of Turner syndrome to investigate how the maternal or paternal origin of the X chromosome affects behavior, such as learning, memory, and social interactions. They will compare the difference in gene expression between the maternal X chromosome and the paternal X chromosome to understand how girls with Turner syndrome exhibit different symptoms. This work could provide insights into sex-specific differences in diseases associated with inheritance of the X chromosome and neurological diseases like autism, and could have major psychosocial, clinical, and societal impacts.