Cytoskeletal control of membrane remodeling

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DESCRIPTION (provided by applicant): Understanding how human cells organize, shape, and move their membrane-bound organelles is one of the most fundamental problems in biology. To address this challenge, my laboratory studies how the actin and microtubule cytoskeletons control membrane remodeling and organelle dynamics. Because the functions of the actin cytoskeleton are crucial for so many cellular and organismal functions, a variety of immunodeficiencies, cardiovascular abnormalities, and neurological defects arise when actin dynamics is disrupted. In human cells, actin filament networks are assembled by proteins called nucleation factors from the Wiskott-Aldrich Syndrome Protein (WASP) family. Despite their importance in remodeling membranes during a wide range of trafficking processes, these nucleation factors have not been well characterized, especially as they relate to mechanisms of human disease. In this proposal, we describe a new genetic disorder that results in a severe neurodevelopmental delay (SND) in humans. This condition is caused by a mutation in WHAMM, a gene encoding one such nucleation factor, and is accompanied by defects in autophagy, a process by which cells degrade their cytoplasmic components. Many neurological and developmental diseases are associated with altered autophagic functions, but the role of the cytoskeleton in autophagosome biogenesis and flux has been largely unexplored. To better understand the role that cytoskeleton-driven membrane remodeling plays in human health, the broad long-term goal of my research is to determine how nucleation factors control membrane dynamics and how alterations in their functions contribute to disease. The specific goals of this project are to determine how WHAMM and other cytoskeleton-associated proteins normally drive remodeling of autophagosome membranes, and to decipher how these functions are altered in SND. These goals will be achieved by completing three specific aims: (1) Determine the molecular and cellular defects that lead to SND, (2) Define the composition and activities of the native WHAMM complex, and (3) Assess the role of small GTPases and phospholipids in cytoskeletal coordination. We hope that our studies will eventually lead to advances in diagnostic tools or therapies for diseases caused by mutations in WHAMM. But since our results will have a broad impact on understanding the cytoskeletal mechanisms that control autophagy, we believe that they may also lead to translational benefits for patients with many other illnesses.