PROJECT SUMMARY
The overarching goal of this five-year Career Development Award proposal is to support Dr. Jillian Ziemanski's
development into an independent ocular surface immunologist with expertise in dry eye disease, particularly
Sjögren's syndrome. Primary Sjögren's syndrome (pSS) is a chronic autoimmune exocrinopathy and epithelitis
that leads to drying of the ocular and oral mucosae. Patients often present with severe dry eye disease that may
be associated with decreased vision, corneal ulceration, and corneal scarring. The complement cascade, though
best known for its role in infection, has been shown to be aberrantly and strongly activated in several autoimmune
diseases. Activation of complement can lead to in situ killing of cells by disruption of their plasma membranes,
removal of viable cells by phagocytosis, and inflammation, a process that, in turn, further upregulates
complement protein production. Inflammation and conjunctival cell death are hallmarks of pSS dry eye disease
(pSS-DE). Further, pSS-DE is known to have a 9:1 predilection for females. The central hypothesis of this project
is that the complement system is primed for activation in all types of inflammatory dry eye disease and may be
further potentiated by estradiol levels. The system, however, likely remains inactive in non-pSS-DE but is
activated in pSS-DE by immune complexes. This activation may serve as a potential biomarker for differentiation
between pSS- and non-pSS-DE and as a mechanism to target for future therapeutic intervention. Therefore, the
Specific Aims for this project are (Aim 1) to evaluate complement protein production by immortalized human
conjunctival epithelial cells stimulated with dry eye-associated cytokines, (Aim 2) to assess differences in total
inducible complement activity of the tears in vitro with respect to serum estradiol levels, and (Aim 3) to assess
differences in complement activation at the ocular surface in pSS-DE versus non-pSS-DE. The training activities
and research project will take place in the interdisciplinary, collaborative environment of the University of
Alabama at Birmingham. The multidisciplinary mentoring and consulting team is comprised of a dry eye disease,
tear film proteomics, and ocular surface expert (Dr. Kelly Nichols, primary mentor); an expert complement
biologist and immunologist (Dr. Alex Szalai, co-mentor); an expert immunologist experienced with flow cytometric
analysis (Dr. Chander Raman, consultant); and an expert in complement-based diagnostic device development
(Dr. Scott Barnum, consultant). Upon completion of this five-year K23 project, Dr. Ziemanski will have had one-
on-one training in complement biology, immunology, tear film proteomics, flow cytometric analysis, and
diagnostic device development. This K23 project will support an R01 submission to fully investigate the
mechanisms of complement activation and regulation on the ocular surface in pSS-DE and will serve as an
impetus to her career as an independent ocular surface immunologist poised to investigate mechanisms of,
assess treatments for, and develop innovative diagnostic devices for pSS-DE.