|AFFILIATIONS||Associate Professor of Clinical Optometry and Vision Science, UC Berkeley
Associate Professor, Departments of Anatomy and Ophthalmology, Proctor Foundation, UCSF
Co-Chief, Dry Eye Clinic, UC Berkeley School of Optometry
Molecular and Cellular Laboratory
Dr. McNamara’s research centers on understanding the role of innate immunity in protecting host epithelial cells from environmental injury. Mucosal epithelial cells interface with the environment at all body surfaces, including the eye. Thus, the mucosa is often the first line of defense against environmental injury. Mucosal cells use a general defense strategy and are believed to play a critical role in regulating the more powerful adaptive immune response. Unfortunately, sometimes the immune system goes into overdrive and creates a pathological state. Examples of this include ocular allergy, dry eye disease, bacterial infection and even cancer. In each of these disease entities there is an immunological component that either initiates or enhances the disease state. Dr. McNamara’s work focuses on dissecting the molecular events that underlie early immune responses. Her research program involves clinical studies of the human ocular surface, as well as both in vivo and in vitro studies of the immune pathways that promote inflammation in the pathological state. This work will lead to a better understanding of the molecular patterns that contribute to pathology and suggest new strategies for modulating the response in favor of the host
Pathogenesis of autoimmune-mediated eye disease
One of the most debilitating forms of dry eye, known clinically as keratoconjunctivitis sicca (KCS), results from autoimmune diseases that affect the lacrimal gland and ocular surface. Sjögren’s syndrome (SS) is a prime example where infiltration of the lacrimal gland with lymphocytes causes recalcitrant dry eye. To explore the dynamics of dry eye in autoimmune diseases like SS, my laboratory uses a mouse model to mimics the clinical characteristics. We have shown a role for auto antigen-primed, CD4+ T lymphocytes in promoting ocular surface damage in autoimmune dry eye and have been able to extend these findings to human patients with SS. Moreover, we have gone on to identify specific inflammatory proteins and intracellular intermediates that connect T cell infiltration to KCS. Among these intermediates, we found a key role for the inflammatory cytokine, interleukin 1β and tissue macrophages. We are currently pursuing studies that include both pharmacological and genetic alteration of interleukin-1 and macrophage signaling.
Sjögren’s International Collaborative Clinical Alliance (SICCA)
My experience in the area of autoimmune ocular surface disease extends into the clinical arena through my work with SICCA. As a SICCA investigator, I collect clinical data and biospecimens for the Sjögren’s Syndrome Registry. In the past two years, I have co-authored SICCA publications that describe an ocular scoring system for dry eye disease and a new classification criteria for the diagnosis of SS.
Smoke-Induced Lung Cancer: Role of EGFR, MUC1 and Catenins
Within the past six years, my research program has expanded into the area of cancer research. Specifically, my laboratory is focused on deciphering the stress response of airway mucosal epithelial cells to toxins/carcinogens contained in tobacco smoke. Smoking represents the single most important carcinogenic exposure and is the leading cause of cancer-related mortalities. In order to identify drug targets that can be exploited by pharmaceutical companies to alleviate and/or prevent lung cancer caused by tobacco smoke, my lab uses a novel, 3-dimensional experimental model of stratified bronchial epithelial cells to simulate the in vivo airway. Cells are exposed to smoke using a fast, easy, and reproducible method, which offers the opportunity to perform manipulations at a molecular level. Using this model, we have explored the early steps in smoke-induced lung cancer. We discovered that tobacco smoke disrupts the interactions between mucosal epithelial cells and liberates the cell junction protein, β-catenin. Once released from the cell surface, β-catenin is transported to the nucleus where it turns on pro-tumor genes. These studies suggest that early alterations by smoke induce pre-neoplastic changes of the healthy lung that have the functional capacity to promote tumorigenesis. Moreover, we found that another cell junction protein, p120catenin, is essential for promoting migration of airway epithelial cells in response to cigarette smoke. A deeper understanding of smoke-induced cell migration may provide a platform for screening new drug candidates that suppress tumor progression and cell migration in metastatic disease.
Vijmasi T, Chen F, Chen YT, Gallup M, McNamara NA: Topical administration of IL-1 receptor antagonist as a therapy for aqueous-deficient dry eye in autoimmune disease. Mol Vis 2013, in press.
Zhang L, Gallup M, Zlock L, Basbaum C, Finkbeiner WE, McNamara NA: Cigarette Smoke Disrupts the Integrity of Airway Adherens Junctions through the Aberrant Interaction of P120-catenin with the Cytoplasmic Tail of MUC1. J Pathol, 229:74-86, 2013.
Zhou D, Chen YT, Chen F, Gallup M, Vijmasi T, Bahrami AF, Noble L, Rooijen N, McNamara NA: Critical involvement of macrophage infiltration in the development of Sjögren’s syndrome-associated dry eye. Am J Pathol 181:753-60, 2012.
Chen YT, Lazarev S, Bahrami AF, Noble LB, Zhou D, Yadav M, McNamara NA: Interleukin-1 receptor signaling mediates the functional interplay between autoreactive CD4+ T cells and ocular resident cells during keratinizing squamous metaplasia in Sjögren’s syndrome. Lab Invest 92:556-70, 2012.
Zhang L, Gallup M, Zlock L, Finkbeiner WE, McNamara NA: Cigarette smoke promotes human bronchial epithelial migration through temporal coordination of p120-catenin dependent and independent pathways. Biochem Biophys Res 417:49-55, 2012.
Shiboski SC, Shiboski CH, Criswell L, Baer A, Challacombe S, Lanfranchi H, Schiødt M, Umehara H, Vivino F, Zhao Y, Dong Y, Greenspan D, Heidenreich AM, Helin P, Kirkham B, Kitagawa K, Larkin G, Li M, Lietman T, Lindegaard J, McNamara NA, Sack K, Shirlaw P, Sugai S, Vollenweider C, Whitcher J, Wu A, Zhang S, Zhang W, Greenspan J, Daniels T: American College of Rheumatology classification criteria for Sjögren’s Syndrome: A data-driven expert consensus approach in the Sjögren’s International Collaborative Clinical Alliance Cohort. Arthritis Care Res 64:475-87, 2012.
Daniels TE, Cox D, Shiboski CH, Schiodt M, Wu A, Lanfranchi H, Umehara H, Zhao Y, Challacombe S, Lam MY, De Souza Y, Schiodt J, Holm H, Bisio PA, Gandolfo MS, Sawaki T, Li M, Zhang W, Varghese-Jacob B, Ibsen P, Keszler A, Kurose N, Nojima T, Odell E, Criswell LA, Jordan R, Greenspan JS; Sjögren’s International Collaborative Clinical Alliance Research Groups. Associations between salivary gland histopathologic diagnoses and phenotypic features of Sjogren’s syndrome among 1,726 registry participants. Arthritis Rheum 63:2021-30, 2011.
Chan MF, Sack RA, Quigley D, Sathe S, Vijmasi T, Holsclaw D, Strauss EC, McNamara NA: Protein array analysis of immune and angiogenic modulators in ocular cicatricial pemphigoid. Opt Vis Sci 88:1005-9, 2011.
Chen YT, Nikulina K, Lazarev S, Gallup M, McNamara NA: Interleukin-1 as a phenotypic immuno-modulator in keratinizing squamous metaplasia of the ocular surface in Sjögren’s syndrome. Am J Pathol 177:1333-43, 2010. PMID: 20696775.
Chen YT, Gallup M, Nikulina K, Zlock L, Finkbeiner W, McNamara NA: Cigarette smoke causes EGFR-mediated depolarization of apical MUC1-mucin and junctional b-catenin in the human airway epithelium. Am J Pathol 177:1255-64, 2010. PMID: 20651243.
Whitcher JP, Shiboski CH, Shiboski SC, Heidenreich AM, Kitagawa K, Zhang S, Hamann S, Larkin G, McNamara NA, Greenspan J, Daniels TE: A simplified quantitative method of assessing keratoconjunctivitis sicca from the Sjogren’s Syndrome International Registry. Am J Ophthalmol 149:405-15, 2010.
Li S, Gallup N, Chen Y-T, McNamara NA: Molecular mechanisms of proinflammatory cytokine-mediated squamous metaplasia in human corneal epithelial cells. Invest Ophthalmol Vis Sci 51:2466-75, 2010.
Liu H, Begley CG, Chen M, Bradley A, Bonanno JA, McNamara N, Nelson JD, Simpson T: A link between tear instability and hyperosmolarity in dry eye. Invest Ophthalmol Vis Sci 50:3671-9, 2009.
Chen YT, Li S, Nikulina K, Porco T, McNamara NA: Immune profile of squamous metaplasia development in autoimmune regulator-deficient dry eye. Mol Vis 15:563-576, 2009.
Sack R, Sathe S, Beaton AR, McNamara N, Fleiszig S, Ni M. Protein array characterization of bioactive proteins secreted by immortalized human corneal epithelium in response to pseudomonas constituents. Curr Eye Res: 34:92-8, 2009.
Li S, Nikulina K, DeVoss J, Wu A, Strauss EC, Anderson MS, McNamara NA: Small protein rich-protein 1B (SPRR1B) is a biomarker for squamous metaplasia in dry eye disease. Invest Ophthalmol Vis Sci 49:34-41, 2008.
Li S, Sack R, Vijmasi T, Sathe S, Beaton A, Quigley D, Gallup M, McNamara NA: Antibody protein array analysis of the tear film cytokines. Optom Vis Sci 85:653-60, 2008.
Sack RA, Conradi L, Beaton A, Sathe S, McNamara N, Leonardi A: Antibody array characterization of inflammatory mediators in the allergic and normal tears in the open and closed eye environments. Exp Eye Res, 85:528-38, 2007.
Maltseva I, Fleiszig SM, Evans DJ, Kerr S, Sidhu SS, McNamara NA, Basbaum CB: Exposure of human corneal epithelial cells to contact lenses in vitro suppresses the upregulation of human beta-defensin-2 in response to antigens of Pseudomonas aeruginosa. Exp Eye Res, 85:42-53, 2007.
McNamara N, Gallup M, Sucher A, Maltseva I, McKemy D, Basbaum C: AsialoGM1 and TLR5 cooperate in flagellin-induced nucleotide signaling to activate Erk1/2. Am J Respir Cell Mol Biol, 34:653-660, 2006.
Dasari V, Gallup M, Lemjabbar H, Maltseva I, McNamara N: EMT in lung cancer: Is tobacco the “smoking gun”? Am J Respir Cell Mol Biol, 35:3-9, 2006.
McNamara NA, Andika R, Kwong M, Sack RA, Fleiszig SM: Interaction of Pseudomonas aeruginosa with human tear fluid components. Curr Eye Res 7:517-525, 2005.
McNamara N, Gallup M, Khong A, Maltseva I, Fahy J, Dolganov G, Basbaum C: Adenosine upregulation of the mucin gene, MUC2, in asthma. FASEB J 18:1770-2, 2004.
McNamara N: Innate Defense of the Ocular Surface. Eye Contact Lens 29: S10-13, 2003.
McNamara N, Sack R, Fleiszig SMJ: Mucin-Bacterial Binding Assays. Chapter 35. T. Corfield, ed. Glycoprotein Methods and Protocols, Methods in Molecular Biology. Humana Press, Totowa, NJ, 125:429-437, 1999.