Center/Research Area Affiliations

• Cornea Center of Excellence
• Infectious Disease Institute
• Ocular Regenerative Medicine Institute

Biography

At Schepens Eye Research Institute of Mass Eye and Ear, Dr. Dartt studies the neural regulation of tear production, focusing on the cellular signaling pathways that nerves and growth factors use to stimulate protein secretion from the lacrimal gland and mucin secretion from conjunctival goblet cells. Her goal is to identify the signaling pathways that stimulate secretion under normal conditions and to determine the dysfunction related to dry eye, LASIK, allergic conjunctivitis, and infection. A major area of her research is the role of conjunctival goblet cells in inflammation and the active resolution of inflammation in allergic conjunctivitis and bacterial infection.

She has been continuously funded by NIH since 1980. Dr. Dartt directed the Institute’s Department of Defense Research Program and chaired six Military Vision Research Symposia. She chaired the ARVO Cornea Program Planning Committee. She is a Vice President for the International Society for Contact Lens Research. She chaired the 2016 Cornea, Biology and Pathobiology, Gordon Research Conference. She is on the editorial board for multiple vision science journals. She served on the NIH Study Section Diseases and Pathology of the Visual System (DPVS), and from 2004 to 2009, she was the Associate Director of Research, Acting Director of Research, and Director of Scientific Affairs at Schepens Eye Research Institute of Mass Eye and Ear.

Education

1978: PhD, Physiology, University of Pennsylvania

Postgraduate Training

1978-1979: Postdoctoral Fellow in Medical Physiology, University of Copenhagen in Denmark

1979-1981: Postdoctoral Fellow in Physiology, Tufts University School of Medicine

Honors

2010: Best Oral Presentation,Third Military Refractive Surgery Meeting

2009: Best Oral Presentation, Association for Research in Vision & Ophthalmology

2004: Spirit Award,Schepens Eye Research Institute of Mass Eye and Ear

2001: Lew R. Wasserman Award,Research to Prevent Blindness

1979-1981: Postdoctoral Fellowship,National Institutes of Health

1978-1979: Fellowship, George G. MarshallScandinavian-American Foundation

Nerve and Lacrimal Gland Dysfunction in Dry Eye

Hematoxyline and eosin stain of lacrimal glands of wild type and TSP1-/- miceglandsWorking with Dr. Sharmila Masli at Boston University School of Medicine, Dr. Dartt and colleagues have developed a new model of dry eye disease with the thrombospondin-1 (TSP-1)-/- mouse. TSP-1 is critical for the maintenance of an anti-inflammatory environment, and its absence leads to a pro-inflammatory environment. As the mice age, the lacrimal gland is infiltrated by immune cells, lacrimal gland protein in tears decreases, the volume of the tear fluid increases, and the ocular surface becomes damaged. These changes are consistent with dry eye.

Furthermore, Dr. Masli in conjunction with Dr. Dartt’s laboratory, found that a polymorphism of TSP-1 decreases the amount of TSP-1 and increases the amount of the pro-inflammatory cytokine IL-1b in human conjunctival cells predisposing them to dry eye after refractive surgery. This finding suggests that their mouse model is highly relevant to human dry eye. Using the TSP-1-/- mouse as a model of dry eye, they found that there were multiple mechanisms by which lacrimal gland function was altered. These mechanisms included a change in the number and function of sensory trigeminal ganglia nerves and efferent parasympathetic nerves in the lacrimal gland, and the number and function of the lacrimal gland myoepithelial cells. Finally, the turnover of lacrimal cells was altered. They suggest that there are multiple “hits” caused by the lack of TSP-1 that lead to lacrimal gland dysfunction. Dr. Dartt is exploring in depth the cellular signaling mechanisms that the lack of TSP-1 affects.

Role of Conjunctival Goblet Cells in Allergic Inflammation and Its Resolution

Counter regulation of H1 receptor by beta-adrenergic kinase and protein kinase CDr. Dartt’s laboratory was the first to culture human, rat, and mouse conjunctival goblet cells—enabling the researchers to analyze the function of these cells on a molecular level. Conjunctival goblet cells secrete a high molecular weight gel-forming mucin that protects the ocular surface from the many varied challenges of the environment. These cells have developed multiple mechanisms and signaling pathways to secrete their protective mucin.

Dr. Dartt previously found that neurotransmitters from parasympathetic nerves stimulate conjunctival goblet cell secretion using specific signaling pathways.

Currently, Dr. Dartt and colleagues are investigating the role of conjunctival goblet cells in ocular surface inflammatory diseases. They have first focused on allergic conjunctivitis. Working with Drs. Charles Serhan and Nan Chiang from Harvard Medical School, they found that allergic mediators, such as histamine and leukotrienes, directly stimulate goblet cells via their receptors to cause mucin secretion.

Dr. Dartt also discovered that goblet cell secretion in the context of allergic conjunctivitis can be regulated by pro-resolution mediators, such as resolvins. Using goblet cells, her group found that resolvins use their receptors to counter-regulate the activation of the H1 histamine receptor to block secretion.

Dr. Dartt and colleagues continue to investigate how resolvins interact with the receptors of inflammatory mediators to down-regulate their action. In addition, they are collaborating with Dr. Daniel Saban of Duke University to study the role of goblet cells, inflammatory mediators, and pro-resolution compounds in a mouse model of allergic conjunctivitis.

NRLP3 Inflammasome: A Protective Response of Conjunctival Goblet Cells to Bacterial Infection

Goblet cells also protect the ocular surface from bacterial infection, especially that of Staphlococcus aureus (S. aureus). Nod-like receptors (NLR) along with Toll-like receptors (TLR) respond to different types of bacteria to protect cells from infection. Conjunctival goblet cells are no exception. These cells contain the NRLP3 type of inflammasome that responds to S. aureus inducing the synthesis of pro-IL-1band activating caspase-1 to cause cleavage of mature IL-1b. The mature IL-1b then activates an inflammatory response to clear the bacteria from the ocular surface. Dr. Dartt is currently comparing the effects of commensal and pathogenic bacteria and the cellular mechanisms by which these bacteria work, as well as the role of the S. aureus alpha-toxin.

Identification of Lacrimal Gland Stem Cells

The lacrimal gland has proliferative potential and contains a population of stem cells. Dr. Dartt works with Dr. Helen Makarenkova on lineage tracing of stem cells in the lacrimal gland. Their work suggests that a population of myoepithelial cells serve as the progenitor cells of the lacrimal gland and this is dependent upon the stage in development. Progenitor cells can be isolated from both rat and mouse lacrimal glands and can be differentiated into different cell types. As TSP-1-/- mouse lacrimal glands have altered cellular turnover, they have isolated progenitor cells from this mouse model to determine if they are altered with disease progression and differ from progenitor cells isolated from wild type mice. They plan to continue determining the complex role that myoepithelial cells play in the production and repair of different population of lacrimal gland cells.

Predicting Dry Eye after Refractive Surgery

Dry eye is a complication in almost every individual who undergoes refractive surgery. Although most cases of dry eye are temporary, some people may experience chronic symptoms. In conjunction with the military and the refractive surgery service at Fort Belvoir (formerly the Walter Reed Army Medical Center), Dr. Dartt and colleagues are studying a large cohort of patients to determine what factors predisposed them to chronic dry eye after refractive surgery. They investigated the tear film, cornea, and goblet cells of the conjunctiva.

Finding Artificial Scaffolds for Growth and Transplantation of Conjunctival Goblet Cells

The conjunctival goblet cells and their production of the large gel-forming mucin MUC5AC are critical for the health of the entire ocular surface. Dr. Dartt, along with Drs. Tor Utheim, Ola Nilsen, and Jon-Roger Eidet at the University of Olso, identified several novel types of artificial chemical and natural scaffolds that supported the growth of conjunctival cells, including a substantial population of goblet cells. Several of the types of scaffolds that are used for many other tissues do not support the growth of conjunctival goblet cells, but silk fibroin, collagen hydrogel, and titanium oxide based scaffolds were very successful. They plan to continue this work to enable transplantation into injured eyes.

Current Members of the Vecellio Dry Eye Laboratory

Senior Scientist

• Darlene Dartt, PhD

Research Associate

• Jeffrey Bair, BS

Visiting Scientists

• Tor Utheim, MD, PhD
• Oeygunn Utheim MD

Alumni

More than 34 trainees have worked in Dr. Dartt’s laboratory.