2014 — 2018 |
Campellone, Kenneth G |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cytoskeletal Control of Membrane Remodeling @ University of Connecticut Storrs
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.
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2016 — 2021 |
Campellone, Kenneth G |
K02Activity Code Description: Undocumented code - click on the grant title for more information. |
Cytoskeletal Functions in Cell Aging and Disease @ University of Connecticut Storrs
7. PROJECT SUMMARY 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. As cells age, their ability to properly regulate these processes changes. This is especially true for kidney cells and immune cells, as a variety of renal and inflammatory diseases develop with age. However, the differences in cytoskeletal functions that give rise to these cellular changes during the aging process are poorly understood. 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 processes, these nucleation factors have not been well characterized, especially as they relate to aging and mechanisms of human disease. I have a long-standing interest in determining how the cytoskeleton drives membrane dynamics in normal cells, and how these functions are altered in the context of infectious and genetic diseases. The immediate goal of this Career Development Award is to allow me to initiate another avenue of investigation on the role of the cytoskeleton in cell aging so that I can achieve my long-term goal of leading a lab which studies cytoskeletal functions in health, aging, and disease. These goals will be achieved by completing four specific aims: (1) Define roles for actin nucleation factors and regulators of autophagy in kidney disease, including Nephrocerebellar Syndrome (NCS); (2) Determine functional links between the cytoskeleton, autophagy, cytokine secretion, and inflammation during infection and aging; (3) Deepen my training in the biology of aging through collaborative training experiences at the Jackson Laboratory's Nathan Shock Center of Excellence in the Basic Biology of Aging and at the Center on Aging at the UConn Health Center; (4) Develop into an independent investigator in the basic biology of cell aging. Given my expertise in cytoskeletal biology, plus my existing grant on the role of actin nucleation in autophagy and disease, my lab is uniquely positioned to provide key mechanistic insights into the relationships among actin nucleation factors, autophagy, kidney function, inflammation, and aging.
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