Yulu Cherry Liu, Ph.D.

Supervisor(s): Dr. Adrian Salic
Award: KRESCENT Post-Doctoral Fellowship
Institution: Harvard Medical School
Year: 2016-2019
Project Title: Understanding chronic kidney diseases caused by defective retrograde trafficking in the primary cilia, and devising strategies to correct it

Lay Summary

In the human body, the main function of cilia is to serve as “cellular antennas”, for detecting and interpreting various environmental signals. Cilia are vital for proper development and function of multiple organs and tissues. Cilia defects lead to human diseases collectively termed ciliopathies, which encompass a wide spectrum of symptoms, including retinal degeneration, polycystic kidney, and skeletal abnormalities. In spite of their critical importance, how cilia defects cause disease remains poorly understood. The main goal of the present proposal is to decipher the molecular link between cilia and disease. Specifically, I aim to elucidate how mutations that affect a critical ciliary process called retrograde trafficking, impair the Hedgehog cell-cell signalling pathway, which plays fundamental roles in embryonic kidney development. To achieve my aim, I propose taking a multidisciplinary approach, combining state-of-the-art biochemistry, proteomics, and chemical biology. First, I will employ complementary strategies to define the molecular organization and protein-protein interactions of the Hedgehog pathway in primary cilia, and to uncover Hedgehog regulation by retrograde trafficking. Next, I will determine precisely how impaired retrograde trafficking, as it occurs in chronic kidney disorders, leads to defective Hedgehog signalling. Finally, through screening and chemical biology, I will discover and characterize small molecules capable of “rescuing” Hedgehog signalling compromised by defective retrograde trafficking. Together, my findings will make important strides toward understanding how ciliopathies develop, and towards novel strategies for treating these devastating human conditions.