Miniscule signaling molecule plays critical role in certain acute and chronic diseases

Scientists seeking to harness the healing power of a miniscule signaling molecule that plays a critical role in certain acute and chronic diseases have been awarded a Program Project Grant (PPG) of nearly $10 million by the National Heart, Lung and Blood Institute of the National Institutes of Health.

The 5-year grant is being used to advance the development of therapies based on the molecule known as adenosine by investigators at The University of Texas Health Science Center at Houston (UTHealth) and University of Colorado Denver Anschutz Medical Campus. The grant runs through May 31, 2018.

When adenosine production is stimulated, it triggers events that increase blood flow and oxygen levels to promote healing. This is beneficial for acute injuries requiring extra blood and oxygen to heal. But it creates challenges with chronic conditions because too much adenosine can result in excessive inflammation and tissue remodeling, a process known as fibrosis.

"Adenosine is produced to help orchestrate the processes that facilitate healing," said Michael Blackburn, Ph.D., the study's principal investigator and a professor in the Department of Biochemistry and Molecular Biology at the UTHealth Medical School.

Blackburn and Yang Xia, M.D., Ph.D. of the UTHealth Medical School, and Holger K. Eltzschig, MD, Ph.D. of the University of Colorado are each heading projects tied to adenosine-based therapies. Blackburn's project focuses on adenosine signaling in lung disease. Xia's project centers on sickle cell disease, and Eltzschig's project concentrates on acute kidney injury.

"Our challenge is to figure out how to manipulate adenosine levels for the benefit of a variety of conditions," Blackburn said. "By combining our expertise and efforts, we hope to develop adenosine-based therapies for lung disease, sickle cell disease and acute kidney injury."

Lung disease is the third leading cause of death in the United States, trailing only heart disease and cancer. Adenosine production goes into high gear when your body experiences an oxygen shortage, which is why adenosine plays such an important role in lung disease. Lung disease research is particularly important because there are no cures for many of these diseases. Doctors can treat the symptoms but not the underlying pathologies.

Blackburn, who is a dean of The University of Texas Graduate School of Biomedical Sciences at Houston, said, "Drug companies are starting to develop and promote adenosine-based therapies for potential clinical trials. Achieving the goals put forth in this study will help guide the appropriate usage of these drugs for different diseases." Blackburn is the holder of the John P. McGovern Graduate School of Biomedical Sciences Endowed Distinguished Professorship at UTHealth.

For example, boosting adenosine levels could be a way to treat acute lung and kidney injury; but reducing levels could ameliorate chronic lung diseases such as idiopathic pulmonary fibrosis and pulmonary hypertension.

"Dr. Michael Blackburn's national recognition in the field of adenosine signaling and pulmonary disease has contributed to the successful NIH funding of this program," said UTHealth President Giuseppe Colasurdo, M.D. "We look forward to the successes that may result from this innovative and translational program."

Xia studies adenosine signaling in sickle cell disease, a life-threatening blood disorder affecting millions worldwide. Her laboratory has uncovered a detrimental role of elevated adenosine in sickle cell disease. This discovery points toward novel therapeutic possibilities by targeting adenosine signaling and demonstrates a previously unrecognized beneficial role for adenosine signaling in normal erythrocytes (red blood cells) by triggering oxygen release.

Based on these new discoveries, Xia and her colleagues will conduct preclinical studies to assess the role of adenosine signaling in red blood cells following tissue injury. Her laboratory will also collaborate with the NIH to conduct human translational studies to validate whether adenosine is a pathogenic biomarker correlated to disease severity in sickle cell disease patients.

Like acute lung injury and unlike sickle cell disease, increased adenosine is being eyed as a way to treat acute kidney injury, which is defined as the rapid loss of kidney function. The work being conducted in Eltzschig's lab could provide new approaches to treat acute kidney injury.

Blackburn said researchers will be running tests on the four receptors of the adenosine molecule to see if they can be changed to alter adenosine signaling and whether that affects the course of disease. Findings in animal studies will be confirmed on samples of diseased human tissue.

Rodney Kellems, Ph.D., chair of the UTHealth Department of Biochemistry and Molecular Biology, said the awarding of this Program Project Grant is a well-deserved testament to the past accomplishments and future potential of these three investigators. "With the past as prologue, and with the significant financial support provided by the PPG, we can confidently look forward to an even greater pace of important discoveries from this talented and interactive group," Kellems said.