Could Controlling the p73 Gene be the key to Treating Chronic Lung Disease?



Stony Brook researchers discover p73 as the master regulator of cells that clean our airways

Stony Brook, NY – June 2, 2016 – Rising global air pollution and increasing smoking prevalence in many developing nations will likely lead to a growing incidence of lung diseases such as chronic obstructive pulmonary disease (COPD), which currently affects more than 330 million people worldwide, is the third-leading cause of death and carries an estimated healthcare cost of $2.1 trillion. Treating COPD and other related lung conditions such as asthma, remain challenging. Now Stony Brook University researchers believe the key to discovering better treatments for chronic lung diseases sits with the p73 gene. They found that this gene is the master regulator of a cell type that is responsible for constantly cleaning our airways from inhaled pollutants, pathogens and dust. In an advance online paper published in Genes & Development, they discovered that when p73 is absent, these cells no longer work. This leads to chronic airway infections, which causes irreversible COPD and emphysema and might also promote asthma.

Dr. Ute Moll and paper co-author Dr. Alice Nemajerova (holding a slide) viewing images of tissue where p73 is absent.

The study, led by Professor Ute M. Moll, MD, and research scientist Alice Nemajerova, PhD, from the Department of Pathology at Stony Brook University School of Medicine, unexpectedly identified the p73 gene, a cousin of the p53 tumor suppressor gene, to regulate proper function of airway epithelium in mice and likely also in humans. For more on the research and the findings illustrated in the Genes & Development paper, see this video.

Airways are lined by a specialized barrier epithelium containing about 50 percent multiciliated cells (MCCs). These MCCs feature hundreds of long cilia at their cell surface. Each cilium is a complex nanomachine and together they beat vigorously and synchronously to create a directional conveyor belt that transports inhaled noxious particles back up to mouth and nose, thereby vitally protecting the gas exchanging surfaces of the lung. Dr. Moll and colleagues identified p73 to be the genetic “master switch” for the specific production of cilia in precursor cells destined to become MCC cells.

In the paper entitled “TAp73 is a central transcriptional regulator of airway muticiliogenesis,” Dr. Moll and colleagues found that gene-engineered mice that lacked either the entire p73 gene or the version of the gene called TAp73 suffered from chronic respiratory tract infections due to profound defects in ciliogenesis and complete loss of mucociliary clearance.

“Prior to our work, the genes that govern multiciliogenesis remained poorly understood,” said Dr. Moll. “We found that p73 sits at the top of a hierarchy and directly turns on more than 50 other key genes that control the architecture and movement of cilia. Moreover, when we took the highly defective airway epithelium from p73 knockout mice and inserted the p73 gene back into the cells, they now made a beautiful set of fully functional cilia. This breakthrough in our understanding of p73’s essential role in multiciliogenesis helps to greatly increase our knowledge of this process, which is so central to respiratory health.”

Since their genomic data implies the same pathway in humans, Dr. Moll emphasized that their finding opens the door for large-scale population-based studies of people with chronic lung disease to look for defects in p73-controlled airway function. She added that the data will also help power studies to prophylactically identify healthy persons at risk who carry a defective p73 gene and live in a polluted environment. Moreover, correcting for defective p73 function may be a promising therapeutic strategy for future treatments of COPD-related lung diseases.

###

About Stony Brook University

Part of the State University of New York system, Stony Brook University encompasses 200 buildings on 1,450 acres. Since welcoming its first incoming class in 1957, the University has grown tremendously, now with more than 25,000 students and 2,500 faculty. Its membership in the prestigious Association of American Universities (AAU) places Stony Brook among the top 62 research institutions in North America. U.S. News & World Report ranks Stony Brook among the top 100 universities in the nation and top 40 public universities, and Kiplinger names it one of the 35 best values in public colleges. One of four University Center campuses in the SUNY system, Stony Brook co-manages Brookhaven National Laboratory, putting it in an elite group of universities that run federal research and development laboratories. A global ranking by U.S. News & World Report places Stony Brook in the top 1 percent of institutions worldwide. It is one of only 10 universities nationwide recognized by the National Science Foundation for combining research with undergraduate education. As the largest single-site employer on Long Island, Stony Brook is a driving force of the regional economy, with an annual economic impact of $4.65 billion, generating nearly 60,000 jobs, and accounts for nearly 4 percent of all economic activity in Nassau and Suffolk counties, and roughly 7.5 percent of total jobs in Suffolk County.

Greg Filiano

Media Relations Manager, School of Medicine, Stony Brook University

Office: 631.444.9343

gregory.filiano@stonybrookmedicine.edu