Predoctoral Fellowship – Theoharides Laboratory, Tufts University
This grant provided support for a predoctoral fellowship for a student in Theoharis Theoharides’ lab at Tufts University. Despite the rise in Autism Spectrum Disorders (ASD), characterized by social and stereotypic disabilities, there remains a lack of knowledge regarding disease causes or treatment. Mounting evidence supports the involvement of brain inflammation due to genetic, neurohormonal and environmental factors, as well as the role of immune dysfunction. The affected brain regions are rich in mast cells and microglia, the critical immune cells, which regulate neuronal function in the developing ASD brain. The kinase mammalian target of rapamycin (mTOR), which regulates immune cell proliferation and proinflammatory mediator expression, and the downstream cytoskeletal regulator of secretion, moesin, have recently been linked to ASD. High risk of some ASD subtypes is associated with gene mutations, which increase mTOR signaling and lower the brain moesin levels.
Dr. Theoharides’ laboratory cloned moesin protein and showed that a phosphorylation pattern was linked to inhibition of mast cells. They also reported increased serum levels of neurotensin (NT) in some ASD children, a peptide secreted from neurons and present in the gut and brain. They showed that corticotropin-releasing hormone (CRH) secreted under stress can stimulate human mast cells through a synergistic action with NT leading to proinflammatory mediator release.
Their hypothesis was that hyperactive mTOR and lack of regulation by moesin in mast cells and microglia is the missing link for gene-environmental factor interactions and brain inflammation in some ASD. Their studies were aimed at determining if mTOR and moesin regulate mast cell and microglial activation in response to NT and CRH. Their in vivo studies were aimed at determining the presence of brain inflammation in normal and moesin-deficient mice treated with NT and CRH, and the ASD-relevant concentrations of these triggers.
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