Darlene A. Dartt, Ph.D.

Harvard Medical School

Professor of Ophthalmology

Schepens Eye Research Institute of Massachusetts Eye and Ear

Senior Scientist

Vecillo Dry Eye Laboratory

Harold F. Johnson Research Scholar and Director

Research Summary

Center/Research Area Affiliations

Biography

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. She has been continuously funded by NIH since 1980. Dr. Dartt directed the Institute’s Department of Defense Research Program and chaired five 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.

Download her CV or biosketch [PDF] for more information.

Education

Ph.D., Physiology, University of Pennsylvania (1978)

Postgraduate Training

Postdoctoral Fellow in Medical Physiology, University of Copenhagen in Denmark (1978- 1979)
Postdoctoral Fellow in Physiology, Tufts University School of Medicine (1979-1981)

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. Marshall Scandinavian-American Foundation

Her Story

Dr. Dartt is a cell physiologist who studies the neural regulation of tear production. With the advent of refractive surgery and its ablation of corneal nerves and resultant dry eye, the neural regulation of tear production has taken on new importance. The recent realization that the symptoms of dry are neurally based and that corneal nerves are altered in multiple ocular surface diseases has given considerable significance to her field of research in terms of treating dry eye from multiple pathogenic mechanisms. Dr. Dartt aims to identify the signaling pathways used to stimulate secretion under normal conditions and to determine the dysfunction of these pathways in dry eye, LASIK,allergic eye disease, bacterial infection, and aging.

Among her many research discoveries, Dr. Dartt unraveled novel signaling pathways activated by nerves and growth factors to stimulate lacrimal gland protein and conjunctival goblet cell mucin secretion that contribute to the tear film and the development of potential treatments for dry eye. Dr. Dartt and her laboratory have characterized the three major G-protein-linked signaling pathways that are critical for the regulation of lacrimal gland secretion. Surprisingly, each agonist induces specific stimulatory and inhibitory pathways that regulate the shape of the resultant secretion. Some of the novel findings from this work were highlighted in a focus article in the American Journal of Physiology Cell Physiology (AC Snider and KE Meirer, Am J Physiol Cell Physiol 292:C1-C3, 2006).

Proper activation of signaling pathways activated by G protein-coupled receptors is critical for tear production and is disrupted in disease pathogenesis. The Dartt Laboratory works on murine models of Sjogrens syndrome and aging highlighted the role of nerves in secretory dysfunction and suggested new mechanisms to induce lacrimal gland secretion by bypassing the action of the nerves. Specifically the lab developed cAMP-dependent compounds that activate post-receptor signaling pathways as topical treatments for dry eye syndromes.

Dr. Dartt and her laboratory members are also studying precursor cells isolated from the lacrimal gland that appear to be a subset of myoepithelial cells and could repair the damaged lacrimal gland.

Dr. Dartt's work revolutionized the area of conjunctival goblet cell mucin secretion, as she found that nerves using parasympathetic neurotransmitters stimulate goblet cell secretion that protects the ocular surface. The Dartt lab is the only laboratory able to culture both rat and human goblet cells and to investigate the regulation of proliferation and secretion of these cells in a purified culture. The laboratory studied the cellular signaling pathways used by G protein-linked agonists and growth factors to stimulate goblet cell mucous production. One of Dr. Dartt's articles in Experimental Eye Research was noted at the 2008 International Conference on Eye Research to be one of that journal’s most highly cited recent articles.

The Dartt laboratory recently discovered that the inflammatory and allergic leukotrienes, prostaglandins, and histamine cause goblet cell secretion that can be resolved by the pro-resolving mediators—resolvins and lipoxins—that actively terminate inflammation. This work suggests a pivotal role for goblet cells in ocular surface inflammation that occurs in a plethora of ocular surface diseases.

The laboratory is now able to modulate goblet cell proliferation and secretion to manipulate the mucus layer of the tear film and protect the ocular surface in both health and inflammatory disease. This is also relevant to dry eye after LASIK, as the Dartt laboratory found that the ocular surface does not always recover from the surgery and its sequelae. It may also have applications for ocular allergy, neurotrophic keratitis, and contact lens wear.

Dr. Dartt has been the Principal Investigator on multi-project U.S. Department of Defense grants since 2002, and she was the principal investigator on an NIH roadmap grant for interdisciplinary research on blinding eye diseases. This was one of only 21 grants funded across NIH. Multiple new research collaborations and successful research projects arose from this effort. Dr. Dartt also organized six symposia on the needs of the military vision professionals and served as Editor-In-Chief of the Encyclopedia of the Eye, a four-volume major reference work from Elsevier.

During her career, Dr. Dartt has taught and been a mentor to many young scientists, including medical students, postdoctoral and corneal fellows. She has served as chair of numerous Institute committees, and from 2004-2009 led the research at the Institute as the elected Associate Director of Research, Acting Director of Research, and Director of Scientific Affairs. Dr. Dartt is currently a Senior Scientist at Schepens, and Professor of Ophthalmology at Harvard Medical School. Nationally, she has served on committees for national research societies, editorial boards, NIH study sections, and has served as an officer for national and international research societies. She has close interactions with the University of Oslo Schools of Dental Medicine and Medicine through Tor Utheim MD PhD and is actively participating in the training of multiple medical and graduate students to obtain PhD degrees.

Projects

Research Interests

  • Neural regulation of tear production, goblet cell mucin secretion
  • Lacrimal gland stem cells
  • Allergic conjunctivitis
  • Infectious conjunctivitis
  • Dry eye disease
  • Pro-resolution mediators (resolvins, lipoxins, maresins, annexin)

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

bacterial receptorsGoblet 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-1b and 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 Research Funding

2009-201
National Institutes of Health/National Eye Institute R01-EY019470
Conjunctival goblet cell mucin secretion in inflammation and its resolution
$280,813

The goal of this project is to determine the cellular mechanisms by which pro-inflammatory mediators (such as histamine and leukotrienes) induce goblet cell secretion and anti-inflammatory proresolution compounds attenuate goblet cell secretion to restore the normal, critical mucin layer to the ocular surface and prevent develop of dry eye.
2016-2020
NIH/NEI R01-EY026202: Co-Investigator
Lacrimal gland repair using progenitor cells
The goal of this project is to analyze lacrimal gland progenitor cell populations, determine cell lineage specific changes during dry eye diseases progression, and identify the optimum progenitor cells to repair the "diseased" lacrimal gland.

Publications

Selected Publications

Dr. Dartt has published more than 125 peer-reviewed articles, and 45 books, and chapters. Below is a list of selected publications. View her publications on PubMed or Google Scholar.

  1. English JT, Norris PC, Hodges RR, Dartt DA, Serhan CN. Identification and profiling of special pro-resolving mediators in human tears by lipid mediator metabolomics. Prostaglandins Leukot Essent Fatty Acids. 2017;117:17-27.
  2. Hodges RR, Li D, Shatos MA, Bair JA, Lippestad M, Serhan CN, Dartt DA. Lipoxin A4 activates ALX/FPR2 receptor to regulate conjunctival goblet cell secretion. Mucosal Immunol. 2017;10:46-57.
  3. Gromova A, Voronov DA, Yoshida M, Thotakura S, Meech R, Dartt DA, Makarenkova HP. Lacrimal Gland Repair Using Progenitor Cells. Stem Cenlls Transl Med. 2017;6:88-98.
  4. He M, Storr-Paulsen T, Wang AL, Ghezzi CE, Wang S, Fullana M, Karamichos D, Utheim TP, Islam R, Griffith M, Islam MM, Hodges RR, Wnek GE, Kaplan DL, Dartt DA. Artifical polymeric scaffolds as extracellular matrix substitutes for autologous conjunctival goblet cell expansion. Invest Ophthalmol Vis Sci. 2016;57:6134-6146.

Patents

For a complete list of Dr. Dartt’s patents, download her CV [PDF].

Stimulation of Tear Secretion
Gilbard; Jeffrey P. and Dartt; Darlene A. U.S. Patent 4,745,100. May 17, 1988.

Stimulation of Tear Secretion wtih Phosphodiesterase
Gilbard; Jeffrey P. and Dartt; Darlene A. US Patent 4,753,945. June 28. 1988.

Stimulation of Tear SEcretion with Melanocyte Stimulating Hormones
Gilbard Jeffrey P. and Dartt; Darlene A. US Patent 4,868,154

Stimulation with Cyclic Nucleotides
Gilbard; Jeffrey P., and Dartt; Darlene A. US Patent 4,956,348. September 11, 1990.

Therapeutic Regulation fo Abnormal Conjunctival Goblet Cell Mucous Secretion
Dartt; Darlene A. and Kessler; Timothy L. US Patent 5,545,617. August 13, 1996.

Culture of Goblet Cells
Shatos; Marie A., Dartt; Darlene A., Rios; Jose D. US Patent 7,052,690. May 30, 2006.

Culture of Goblet Cells
Shatos; Marie A., Dartt; Darlene A., Rios; Jose D. US Patent 7,316,927. January 8, 2008.

Laboratory

Current Members of the Vecellio Dry Eye Laboratory

Senior Scientist
Darlene Dartt, PhD

Scientific Associate III/Laboratory Manager
Robin R. Hodges, MS

Research Associate
Jeffrey Bair, BS

Postdoctoral Fellow
Menglu Yang, M.D.

Visiting Scientists
Tor Utheim, MD, PhD
Oeygunn Utheim M.D.

Alumni

More than 34 trainees have worked in Dr. Dartt’s laboratory. To view the complete list of alumni, download her CV [PDF]