Research Project
10227532
Program Summary This is an administrative supplement application to the parent grant Harvard-Vision Clinical Scientist Development Program (NEI 5K12EY016335) with the overarching goal to study the pathogenesis of mustard gas keratopathy and develop effective medical countermeasure against it. The Parent K12 Program is a career development grant offering a customized and structured learning, research, and development environment to a select and diverse group of highly-qualified, clinically-trained scholars and providing them with further mentored research experience to become independent clinical scientists in their respective fields. Since the start of the program in 2004, the overwhelming majority of the scholars have successfully completed the program and received independent federal research funding. The program currently has 3 physician scientist scholars including Jia Yin, MD, PhD, MPH. In her K12 program, Dr. Yin investigates the direct regulation of corneal angiogenesis and the development of neovascularization by corneal nerves, specifically the differential expression of nerve-derived peptides in homeostatic and inflammatory microenvironments and their impact on angiogenesis. Dr. Yin?s K12 award mentors are Dr. Reza Dana (PI of the K12 grant), an expert on ocular immunology, and Dr. Patricia D?Amore, an expert on ocular angiogenesis, at Harvard Medical School. In her K12 pursuit, Dr. Yin found that in response to severe dry eye disease, trigeminal ganglion neurons that supply corneal innervation change their secretory pattern of neuropeptides, leading to a more pro-inflammatory and pro-angiogenic profile. It has been noted that sulfur mustard exposure leads to loss and aberrant regeneration of corneal nerves. But the secretion of neuropeptides by corneal nerves after mustard exposure has not been characterized. In addition, Dr. Yin discovered that alkali chemical injury leads to ocular tissue hypoxia and reversal of hypoxia by a topical oxygenated emulsion effectively ameliorates hypoxia, inflammation, and corneal neovascularization in the eye. Although oxygen therapy has been shown to be effective in reducing ocular complications after thermal and chemical injury and is commonly used in lung damage related to mustard gas exposure, the role of hypoxia and the therapeutic potential of oxygen therapy in mustard gas keratopathy (MGK) have not been studied. Both dry eye disease and alkali burn share many molecular, cellular and clinical similarities with MGK: persistent ocular surface inflammation, infiltration of immune cells, nerve degeneration, loss of the immune and angiogenic privileges of the cornea, and in severe cases limbal stem cell deficiency. The proposed supplement aims to expand the scope of the parent grant to better understand how corneal nerves and angiogenesis interplay in the development of MGK and to explore the role of tissue hypoxia in MGK. Importantly, the supplement will permit us to evaluate the translational potential of restoring neuropeptide balance and oxygen therapy as novel therapeutic strategies for a common chemical warfare agent.
