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Penn cell biologist awarded $5.2 million from NIH for lung regeneration research

October 13, 2016

PHILADELPHIA -Penn Medicine researchers, along with colleagues at Cincinnati Children's Hospital and Boston University, have received a $5.2 million, seven-year grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) to study the cellular and molecular mechanisms that promote lung regeneration. The aim of the grant is to develop treatments for children with congenital lung diseases and adults whose lungs have been damaged from smoking, genetic defects, and acute injury.

The Penn-Cincinnati Children's-Boston University research group is one of seven new research hubs that will comprise the new Progenitor Cell Translational Consortium, bringing together multidisciplinary researchers in the heart, lung, blood, and technology fields from different institutions throughout the country. Recipient institutions will receive a total of $40 million over the next seven years. The Consortium's focus will be on translating advances in progenitor cell biology to new treatments for heart, lung, and blood diseases.

The Penn component of the consortium is led by Edward Morrisey, PhD, the Robinette Foundation Professor of Medicine, a professor of Cell and Developmental Biology, and the director of the Penn Center for Pulmonary Biology, in the Perelman School of Medicine. Morrisey is also the scientific director of the Penn Institute for Regenerative Medicine.

"The aim of our consortium is to harness the innate power of stem and progenitor cells in the lung to promote repair and regeneration and target them using emerging techniques for promoting tissue regeneration," Morrisey said. "We will be examining both pediatric and adult populations since many children suffer from chronic lung diseases such as severe asthma and cystic fibrosis. In adults, we are interested in determining whether we can harness the innate ability of the lung to repair and regenerate to treat chronic lung diseases as well as acute injury." The Penn group will also explore whether new advances in gene editing can be used to treat postnatal lung diseases.

One of the major progenitor cell types that will be targeted by the Penn group is called the alveolar type 2 (AT2) cell. AT2 cells, along with AT1 cells, line the alveoli of the lungs. Alveoli are the tiny air-filled sacs, arranged in clusters in the lungs, in which the exchange of oxygen and carbon dioxide takes place. AT2 cells are responsible for generating pulmonary surfactant, a mixture of proteins and lipids that is necessary for allowing lungs to expand and deflate during every breath as well as fight lung infections. When functioning normally, AT2 cells divide to replace old or damaged lung cells including AT1 cells, maintaining lung health. However, AT2 cell injury can lead to defective regeneration and other diseases including lung cancer and lung fibrosis.

The Penn consortium will work to characterize AT2 cells at multiple levels from mouse and human lungs, seeking to better understand their role in lung function and repair. This information will be used to determine whether AT2 cells can be targeted using gene editing techniques to alter their regenerative potential or correct disease-causing mutations.

The project will concentrate on the role of the ABCA3 gene in AT2 cell biology, mutations in which can cause severe acute and chronic pulmonary disorders in infants and children. ABCA3 mutations account for up to 50 percent of cases of full-term infants with congenital lung disease who are resistant to conventional therapies. At present, there are no proven effective therapies for ABCA3 deficiency other than lung transplantation.

"Using disease-inducing ABCA3 mutations as a paradigm for congenital lung disease, we will target AT2 cells to correct these mutations as well as attempt to promote lung regeneration," Morrisey said. "Ultimately, we hope to use lung stem and progenitor cells for treatment of various forms of lung disease."

The Consortium is funded by the National Heart, Lung, and Blood Institute (U01-HL134745).

University of Pennsylvania School of Medicine

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