The Hartwell Foundation


2014 Biomedical Research Collaboration Award

Memphis, TN, November 30, 2014 -- The Hartwell Foundation officially announced the winners of a Biomedical Research Collaboration Award to Jonathan Sears, M.D., 2011 Hartwell Investigator and Associate Professor, Departments of Ophthalmology and Cell Biology, Case Western Reserve University and Randi Silver, Ph.D., 2010 Hartwell Investigator and Professor, Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University for their proposal “Overcoming Retinopathy of Prematurity and Chronic Lung Disease: Unified Systemic Approach”. The researchers will receive $ 698,407 in combined direct cost over three years. Both Case Western and Cornell are current Hartwell Centers of Biomedical Research Excellence.

Although the retina and lung require approximately 40 weeks for normal development of the fetus, nearly 500,000 babies are born prematurely each year in the United States, representing 1 in 8 of all live births. About 16% of all preterm infants are born at less than 32 weeks gestation, making them vulnerable to blindness from retinopathy of prematurity (ROP) and the consequences of respiratory distress associated with long-term chronic lung disease (CLD). In all premature births, oxygen supplementation (hyperoxia) is a necessary life sustaining measure, but unfortunately for these high-risk babies, toxicity to oxygen may adversely and permanently affect the continued development of the retina and lung.

Jonathan Sears, MD, is Associate Professor of Ophthalmology at the Cole Eye Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. He was a Hartwell Investigator in 2011 for his proposal on “Preventing Retinopathy of Prematurity.” His innovative approach was to “pharmaceutically precondition” severely premature infants to control the growth of retinal blood vessels; effectively “tricking” the premature retina into thinking it is exposed to its normal level of oxygen as a developing fetus. His achievements were to recognize the central role of the liver in retinal blood vessel development and repair, and that stabilization of an oxygen-dependent transcription factor in the liver known as hypoxia inducible factor (HIF) is required for the prevention of oxygen-induced retinopathy in the eye.

Randi Silver, Ph.D., is a Professor of Physiology and Biophysics at Weil Cornell Medical College, Cornell University. She was a 2010 Hartwell Investigator for her proposal on the “Role of? Mast? Cells ?in ?Chronic ?Lung ?Disease ?in? Premature ?Birth ?Infants.” She knew that in the lung of premature babies inflammation can cause irreversible scarring, predisposing them to the development of the two most common lung diseases in the Western World, asthma and chronic respiratory disease. She was also aware that mast cells are present in all tissues of the body, characteristically surrounding blood vessels and nerves near the boundaries between the outside world and the internal milieu; and are prevalent in the lungs between the air sacs and the bloodstream, as well as in the air spaces. As specialized immune cells, mast cells are filled with granules containing different chemical mediators that when released can cause inflammation. Alterations in mast cell density, distribution, and molecular expression of such mediators determine their role in pathology. Her achievement was to recognize that as "trigger" cells capable of eliciting acute and chronic airway constriction, mast cells play an important role in the progression of hyperoxia-induced respiratory disease in prematurity.

Sears and Silver hypothesize that since both ROP and CLD occur as a result of high oxygen, they are likely to have a common biochemical and cellular basis. Together, they seek to exploit a therapeutic pathway that has the potential to prevent both conditions. Their collaboration represents the first unified attempt to determine the mechanism(s) of hyperoxia-induced disease based upon a systems biology approach, as opposed to examining a single manifestation of hyperoxia only from the perspective of the affected tissue.

The unified approach of Sears and Silver will focus on the positive benefits of stabilizing HIF. This transcription factor is a key player in blood vessel (vascular) growth during normal tissue development and possibly mast cell-mediated inflammation and scarring in pathology, as well. As collaborators, they will seek to discern how stabilization of HIF in a peripheral organ can confer protection in both the eye and lung. Based upon their working hypothesis, they will seek to determine how the liver communicates with these target tissues, including the extent of a common mast cell connection with ROP and CLD.

Retinopathy of prematurity (ROP) occurs in premature infants following exposure to high levels of oxygen (hyperoxia). It is caused by the abnormal growth of blood vessels in the light-sensitive tissue layer of nervous tissue at the back of the eye that when damaged causes serious visual impairment or blindness.

Chronic lung disease (CLD), also known as bronchopulmonary dysplasia, is a condition that occurs often in premature infants following forced ventilation and exposure to high levels of oxygen. It is caused by inflammation and scarring of lung tissue that is often not fully reversible, creating chronic difficulty breathing. It may later in life trigger asthma, bronchitis and emphysema.

Fostering collaborations between investigators of complementary scientific strengths is one of the objectives of The Hartwell Foundation in its mission to fund innovative, early-stage applied biomedical research with the potential to benefit children of the United States.

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