Aashish Manglik, M.D., Ph.D.

Research

The Manglik lab will probe how information is conveyed by the Hedgehog signaling pathway, a key regulator of body patterning during embryonic development. When this pathway is activated, a protein called Smoothened switches on a set of regulatory proteins that activate genes involved in cell specialization and proliferation. But what exactly turns Smoothened on and how does an inhibitory protein called Patched participate in pathway activation? Our lab combines a suite of techniques in cell and structural biology, protein engineering, and computational drug discovery to unravel such molecular puzzles. Using recently developed antibodies that lock Smoothened in its active conformation and Patched in its inactive state, we aim to determine the precise three-dimensional structures of these components in action and begin to assess how they function during Hedgehog signaling. The results could lead to innovative therapies for eradicating developmental abnormalities associated with disrupted Hedgehog signaling—or treating cancers, such as basal cell carcinomas, that result when the pathway is activated inappropriately.