L. Hazlett Image l hazlett title

e-mail- lhazlett@med.wayne.edu

Education
B.S., Biology, St. Mary's College, Notre Dame, Indiana, 1966
M.S., Anatomy, Medical College of Georgia, Augusta, Georgia, 1968
Ph.D., Anatomy, Ohio State University, Columbus, Ohio, 1971

Professional and Faculty Appointments
Research Associate, Department of Anatomy, The Ohio State University, Columbus, Ohio, 1970-1971
Assistant Professor, Department of Anatomy, Wayne State University, Detroit, Michigan, 1971-1978
Associate Professor, Department of Anatomy, Wayne State University, Detroit, Michigan, 1978-1984
Professor, Department of Anatomy/Cell Biology, Wayne State University, Detroit, Michigan, 1984-1995
Professor, Department of Ophthalmology, Wayne State University, Detroit, Michigan, 1987-present (Joint Appointment)
Professor, Department of Immunology/Microbiology, Wayne State University, Detroit, Michigan, 1988-present (Joint Appointment)
Professor and Chair, Department of Anatomy/Cell Biology, Wayne State University, Detroit, Michigan 1995-present

Major Research Interests
Ocular infection: molecular and immunopathogenic mechanisms; contact lens-induced ocular infection; Toll-like receptors; neuropeptide regulation of the immune response.

Current Research
Pseudomonas aeruginosa (P. aeruginosa) is a common organism associated with bacterial keratitis, especially in more tropical climates and in extended wear contact lens users. The incidence of microbial keratitis is 25,000-30,000 cases annually with cost of treatment estimated at $15-30 million making the disease of considerable medical and economic impact. In these studies, we are testing the overall hypothesis that after corneal infection with P. aeruginosa, the neuropeptides VIP/PACAP inhibit/ downregulate sustained pro-inflammatory cytokine and nitric oxide (NO) production and upregulate anti-inflammatory cytokine production, leading to the resistance response of BALB/c mice. A corollary to this hypothesis is that inflammatory neuropeptides such as SP/CGRP will have a converse effect, leading to the susceptible response of B6 mice.
The aims of this proposal are:

1) To test the hypothesis that the distribution of neuropeptides VIP/PACAP, SP and CGRP in the cornea will differ both spatially and temporally in BALB/c (resistant) vs. B6 (susceptible) mice after infection with P. aeruginosa.
2) To test the hypothesis that the neuropeptides VIP/PACAP, SP, CGRP and secretoneurin (SN) differentially affect the migration into and arrest of Langerhans cells (LC)) in the infected cornea of B6 vs. BALB/c mice.
3) To test the hypothesis that SP/CGRP promote pro-inflammatory cytokine and chemokine production and the influx and persistence of PMN in the infected cornea of susceptible vs. resistant mice.
4) To test the hypothesis that in infected resistant vs. susceptible mice, VIP/PACAP inhibit sustained macrophage (Mf inflammatory cytokine/chemokine and NO production and enhance anti-inflammatory cytokines such as IL-10.
5) To test the hypothesis that SP/CGRP induce sustained upregulation of adhesion molecules after infection in susceptible vs. resistant mice.
In the proposed studies, a combination of in vivo and in vitro systems will be used to analyze the immunomodulatory activities of these neuropeptides. It is expected that the findings will be particularly significant with respect to management of P. aeruginosa keratitis and should lead to better characterization of molecules which are potential targets for more effective treatment of corneal inflammation.

A second R01 focuses on Toll-like receptor. In the studies, we are testing the overall hypothesis that Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) and their associated molecules (e.g., CD14) play a critical role in the initial (innate) immune response in the cornea and are responsible for the disparate outcome to P. aeruginosa infection of B6 and BALB/c mice. Three aims are proposed that will test the hypotheses that:

1) expression levels/distribution of TLR/IL- 1Rs (TLR-4, -9, ST2 and SIGIRR) and related molecules (CD14, MD2) in epithelium and stroma are disparate in B6 and BALB/c mice in normal and/or P. aeruginose infected cornea.
2) the TLR/IL1-R MyD88 vs. TRIF signaling pathway is preferentially activated in susceptible vs. resistant mice after bacterial infection.
3) adaptive immunity (Th1 vs. Th2 responsiveness) is regulated disparately by TLR/IL-1Rs and their signaling molecules in the infected cornea of B6 vs. BALB/c mice.
Thus, the goal of the studies proposed in this application is to elucidate the role of TLR/IL-1R in the innate and adaptive immune response to experimental P.aeruginosa corneal infection resulting in corneal perforation (B6) vs. healing (BALB/c). In the proposed studies, multiple approaches will be used and include use of both in vivo and in vitro models to test TLR expression levels, distribution, signaling and immunoregulatory properties. It is expected that the findings will reveal potential targets for early intervention and/or treatment of P. aeruginosa keratitis.
Grant Support: 2 NIH (R01 and a P30 grant) and a grant from Ciba Vision-Novartis

References
 1. Hazlett, L.D. The corneal response to Pseudomonas aeruginosa infection. Progress in Retinal and Eye Research, 23(1):1-30, 2004. Medline
 2. Lighvani, S., Huang, X., Trivedi, P.P., Swanborg, R.H. and Hazlett, L.D. Substance P regulates NK cell IFN-g production and resistance to Pseudomonas aeruginosa infection. European Journal of Immunology, 35(5);1567-1575, 2005. Medline
 3. Huang X., Barrett RP., McClellan SA., Hazlett LD. Silencing Toll-like receptor-9 in Pseudomonas aeruginosa keratitis. Invest Ophthalmol Vis Sci. 46(11):4209-16, 2005. Medline
 4. Hazlett, L.D. Disorders of the Ocular Surface 4- Bacterial Infections of the Cornea (Pseudomonas). In: Immune Responses in the Eye II. Eds., Jerry Niederkorn and Henry Kaplan. S. Karger , 2006.
 5. Yu FS., Hazlett LD. Toll-like receptors and the eye. Invest Ophthalmol Vis Sci. 47(4):1255-63, 2006. Medline
 6. Huang X., Hazlett LD., Du W., Barrett RP. SIGIRR promotes resistance against Pseudomonas aeruginosa keratitis by down-regulating type-1 immunity and IL-1R1 and TLR4 signaling. J Immunol. 177(1):548-56, 2006. Medline
 7. Huang X., Du W., McClellan SA., Barrett RP., Hazlett LD. TLR4 is required for host resistance in Pseudomonas aeruginosa keratitis. Invest Ophthalmol Vis Sci. 47(11):4910-6, 2006. Medline
 8. Szliter EA., Lighvani S., Barrett RP., Hazlett LD. Vasoactive intestinal peptide balances pro- and anti-inflammatory cytokines in the Pseudomonas aeruginosa-infected cornea and protects against corneal perforation. J Immunol. 178(2):1105-14, 2007. Medline
 9. Hazlett LD. Bacterial infections of the cornea (Pseudomonas aeruginosa). Chem Immunol Allergy. 92:185-94, 2007. Medline
 10. Hazlett LD., Li Q., Liu J., McClellan S., Du W., Barret RP. NKT cells are critical to initiate an inflammatory response after Pseudomonas aeruginosa ocular infection in susceptible mice. J Immunol. 179(2):1138-46, 2007. Medline

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