Dr. Sullivan is a clinician scientist with training in physiology, endocrinology, and immunology. He was recruited into ophthalmology in 1982. Research in his laboratory has addressed the sex steroid regulation of the ocular surface and adnexa, the interrelationships between sex, sex steroids, and dry eye disease (DED), as well as the role of lubricin on the ocular surface. His studies have involved basic, clinical, epidemiological, and translational aspects, and have required the establishment of new and unique experimental approaches (e.g., lipid analytical, proteomic and molecular biological methods). Of particular interest, Dr. Sullivan’s research findings have led to the development of topical treatments (i.e., androgen, lubricin) that may serve as a potential therapy for both aqueous-deficient and evaporative DED.
Dr. Sullivan and his laboratory personnel have discovered that sex and sex steroid hormones are critical factors in the regulation of ocular surface tissues, as well as in the pathogenesis of DED. They have also discovered that androgens may suppress, and that estrogens may promote, aqueous-deficient and/or evaporative DED.
More specifically, they have shown that sex and sex steroids, as well as neuropeptides and cytokines, regulate the secretory immune system of the eye. This system is designed to protect the ocular surface against bacterial colonization, viral adhesion, parasitic infestation and toxin-induced damage, thereby preserving corneal integrity and preventing severe visual impairment. The results support their hypothesis that the endocrine, neural and immune systems govern ocular mucosal immunity. To help conduct these experiments, they developed a defined culture system for the long-term maintenance of responsive acinar epithelial cells from the lacrimal gland. This accomplishment was commended as one of the foremost achievements in ocular surface research by an NEI National Plan for Vision Research.
They also demonstrated that androgens reduce the inflammation in, and enhance the functional activity of, lacrimal glands in mouse models of Sjögren’s syndrome. These findings are extremely significant, given that no clinical therapy currently exists for this debilitating autoimmune disease, which occurs almost exclusively in women and is one of the leading causes of aqueous-deficient DED in the world. The mechanism(s) involved in this androgen-induced immunosuppression is unknown. However, their evidence indicates that this hormone action is a unique, tissue-specific effect, which is initiated through androgen binding to receptors in lacrimal gland epithelial cells. In addition, they hypothesize that this androgen interaction then causes the altered expression and/or activity of specific genes and proteins in lacrimal tissue, resulting in the reduction of immunopathological lesions and an improvement in glandular function. Their research has supported this hypothesis, which, if true, may lead to the development of unique, therapeutic strategies to safely and effectively treat this chronic and vision-threatening disease.
Dr. Sullivan and his laboratory personnel have shown that androgens regulate the meibomian gland, which is the primary tissue involved in maintaining tear film stability and preventing tear film evaporation. This finding is also very significant, given that relatively little information exists concerning the physiological control of this tissue, and that meibomian gland dysfunction (MGD) is the major cause of evaporative DED throughout the world. Based upon their research, they hypothesize that: [a] androgens regulate meibomian gland function, improve the quality and/or quantity of lipids produced by this tissue and promote the formation of the tear film’s lipid layer; and [b] androgen deficiency, such as occurs during menopause, aging, Sjögren's syndrome, complete androgen insensitivity syndrome and the use of anti-androgen medications, leads to MGD, altered lipid profiles in meibomian gland secretions, decreased tear film stability and evaporative DED. Their data support these hypotheses, and have significantly increased our understanding of the physiological mechanisms controlling the meibomian gland in both health and disease.
In addition to these findings, Dr. Sullivan and his laboratory personnel have immortalized human meibomian gland epithelial cells that function like primary cells. These immortalized cells possess a normal karyotype and respond to numerous agents (e.g., sex steroids, glucocorticoids, pituitary hormones, growth factors, neurotransmitters, bacterial toxins and antibiotics) with alterations in proliferation, differentiation, cAMP accumulation, signaling pathways, gene expression and lipogenesis. These cells represent an ideal preclinical human model for drug discovery.
Dr. Sullivan and his team have created a model of human MGD in vitro. Exposure of the immortalized cells to isotretinoin, a well-known risk factor for MGD in vivo, reduces the activity of survival mediators, inhibits proliferation and leads to cell death. They have discovered topical treatments that may counteract these adverse MGD-inducing effects.
They have also discovered human meibomian gland genes that may promote the development of MGD. Moreover, they have identified genes that may be responsible for the typical absence of intraglandular inflammation and bacterial infection in human MGD, and have revealed novel targets for potential therapeutic intervention.
Dr. Sullivan, in collaboration with others, has shown that DED occurs predominantly in women and that estrogen replacement therapy increases the prevalence of DED signs and symptoms in postmenopausal women. This latter finding is extraordinary, given that many millions of women worldwide are prescribed estrogen to alleviate menopausal symptoms and are therefore at heightened risk of developing DED. The precise mechanism(s) underlying the sex-related difference in, and the estrogen effect on, DED prevalence is unclear. However, they hypothesize that: [a] androgen deficiency and estrogen use are key factors in the predominance of DED in women; and [b] sex, androgen and estrogen effects are mediated through the regulation of gene expression in the cornea and the lacrimal and meibomian glands. Their research supports these hypotheses, which, if correct, may be translated into new insights into how estrogens influence ocular tissues, and how these hormones may contribute to the etiology of DED.
Recently, Dr. Sullivan and his group have discovered that: [a] lubricin, a boundary lubricant, is transcribed, translated, and expressed by human ocular surface epithelia; [b] lubricin presence significantly reduces friction between the human cornea and conjunctiva; and [c] lubricin deficiency may play a role in promoting corneal damage. Overall, they believe that lubricin may be an important barrier to the development of corneal and conjunctival epitheliopathies that may occur in DED and contact lens wear.
Dr. Sullivan is a Founder, recent President, and current Chairman of the Board of Directors of the Tear Film & Ocular Surface Society (TFOS), a nonprofit organization that was created to advance the research, literacy, and educational aspects of the scientific field of the tear film and ocular surface throughout the world. He has organized 8 International Conferences, overseen the awarding of more than 225 Young Investigator Awards, and organized the TFOS International Workshops on Dry Eye (“DEWS”), Meibomian Gland Dysfunction, Contact Lens Discomfort and DEWS II. These global workshops have involved the efforts of 60-150 scientific and clinical experts, each required two to three years to complete, and all led to the publication of major reports. Through TFOS he has helped to promote increased international awareness of external eye diseases, enhance governmental funding for tear film and ocular surface research, stimulate the development of therapeutic drugs and diagnostic devices, and influence the design and conduct of clinical trials of novel treatments for ocular surface disorders. TFOS has a distribution to ~8,000 basic scientists, clinical researchers and industry representatives in more than 80 countries.
Within the Schepens Eye Research Institute of Mass. Eye and Ear, Dr. Sullivan has served as the Head of the Research Council (i.e. Faculty Senate), the Director of the Center for Corneal and External Eye Disease Research, the Head of the Immunology Unit, and the Leader of the Immunity, Inflammation and Transplantation Focus Group. He also chaired the Technology Transfer Committee for more than 10 years and helped to create the Joint Clinical Research Center and the Corporate Alliance Program at Schepens Eye Research Institute of Mass. Eye and Ear.
Dr. Sullivan has also chaired the Medical and Scientific Advisory Board of the Sjögren's Syndrome Foundation, and was a Co-Chair of the Cornea Annual Program Committee of the Association for Research in Vision and Ophthalmology. He has acted as a reviewer for research grant proposals for the National Institutes of Health, the Concerted Action Program of the Ministry of Education of Flanders and the USA Veterans Administration, served on the Fellowship Review Panel for the Fight for Sight Research Division of the National Society to Prevent Blindness, and assisted as an editorial referee for many ophthalmic, immune, and endocrine journals.
Novel Treatment for Ocular Burn Injuries
Burns are among the most grievous of all injuries, and are one of the most common types of trauma in the world. Burns of the eyes, in particular, may have devastating, sight-threatening effects. These injuries may lead to the development of ocular surface-lid adhesions (i.e. symblephara), dry eye disease (DED), eyelid contractures, increased intraocular pressure (IOP), and glaucoma. The immediate result of ocular burn injury may be loss of vision. The later result may be continuing visual impairment or blindness, loss of career, significant lifestyle changes, and disfigurement. Dr. Sullivan and his team hypothesize that lubricin, the body’s extraordinary anti- adhesive, anti-friction and anti-inflammatory protein, will serve as a safe and effective treatment for major ocular sequelae of burn injuries (e.g., alkaline), including symblephara, DED, increased IOP and glaucoma. We are testing our hypothesis is an animal model.
Regulating the Meibomian Gland in Health and Disease
Meibomian glands (MGs) play a critical role in the health and well-being of the ocular surface. MG epithelial cells secrete a proteinaceous lipid mixture (meibum) that provides a clear optical surface for the cornea, interferes with bacterial colonization and retards tear overflow. These MG secretions also promote the stability and prevent the evaporation of the tear film. Conversely, MG dysfunction (MGD), and the resulting meibum insufficiency, destabilize the tear film, increase its evaporation and osmolarity, and are the major cause of DED in the world. Given the importance of the human MG, it is amazing that, until recently, almost nothing was known about the regulation of this tissue. Further, there is no global cure for MGD. Our goal is to advance our understanding of the regulation of MG function and the processes underlying MGD and evaporative DED. Dr. Sullivan and his team believe that their efforts may lead to the identification of novel therapeutic strategies to treat MGD and evaporative DED.
Current Research Funding
|Novartis: Principal Investigator (PI)
Licensing of lubricin for ophthalmic indications
|Lubris BioPharma Donation: PI
|NIH R21: PI
Cationic amphiphilic drugs for the treatment of meibomian gland dysfunction
|Margaret S. Sinon Scholar in Ocular Surface Research Fund, Schepens Eye Research Institute of Mass. Eye and Ear