PHILDELPHIA - University of Pennsylvania School of Medicine scientists have been awarded $6.7 million from the National Institute of General Medical Sciences to investigate the role of molecular motors in cell biology. With this grant, Yale E. Goldman, MD, PhD, Director of the Pennsylvania Muscle Institute, Erika L.F. Holzbaur, PhD, Professor of Physiology, and E. Michael Ostap, PhD, Associate Director, Pennsylvania Muscle Institute and Professor of Physiology, will continue their studies of cytoskeletal motors that function in cellular processes of medical importance, including those implicated in neurological disorders and diabetes. Cytoskeletal motors are nano-scale molecular machines that drive the movements of components within cells. This award also supports scientific research directed by Henry Shuman, PhD, Associate Professor of Physiology, and Tatyana Svitkina, PhD, Assistant Professor of Biology, to provide state-of-the-art nanotechnology and cell biological tools.
“In the last few years it has become obvious that molecular motors are important to such diseases as neurological and metabolic disorders, deafness, blindness, and cancer,” says Goldman. “Now we have a research program that approaches the role of motors in cell biological processes from different levels.” The team will be studying molecular motors at the fundamental biophysical level; constructing patterns of cytoskeletal filaments to measure the behavior of motors in a controlled way; and ultimately, looking at live cells to study transport in such cell types as neurons and fat cells, and how mistakes in transport relate to neurological disorders and diabetes, respectively.
“The real strength of this grant is that we have the nanotechnology tools to look at biology on this scale, along with an understanding of how motors work within a cell, to finally put all of this together in a medically relevant way,” says Ostap.
For example, about a year ago Ostap published in Science about his lab’s discovery that the activity of a nanometer-sized molecular motor called myosin-I is regulated by force. The motor puts tension on cellular springs that allow vibrations to be detected within the body. This finely tuned regulation has important implications for understanding a wide variety of basic cellular processes. In two specific cases, myosin I puts tension on the specialized spring-like structures in human ears that enable hearing and maintenance of balance, and also has a role in delivering the proteins that pump glucose into cells in response to insulin.
The proper working of two other microtubule motors, dynein and kinesin, is important for the transport of cellular cargo. These motors respond to obstacles on their molecular tracks very differently. Goldman and Holzbaur reported in Science, also last year, that dynein reverses direction or goes around the protein tau, whereas tau pries kinesin away from the track. Mislocation of tau on the microtubule track in some neurodegenerative diseases may disrupt normal nourishment and waste removal in nerve cells.
“Considering molecular motors as ‘nature's nano-machines’ helps us gain a basic understanding of their biophysical mechanisms and their roles in normal and diseased cell biology,” points out Goldman.