The long-term objective of this grant application is to study the molecular mechanism of scarring in the conjunctiva of patients with ocular cicatricial pemphigoid (OCP). Severe conjunctival scarring leads to blindness in about 25% of OCP patients, inspite of aggressive systemic therapy.
The aim of this grant proposal is to identify some of the factors that are involved in the inflammatory and fibrotic stages, and define their role in the scarring process. Investigators studying ocular scarring in toxic epidermolysis necrosis, Steven-Johnson syndrome, epidermolysis bullosa acquisita, and other similar diseases will significantly benefit from these experiments. The PI has focused on only few molecules in an attempt to define a model system. Our preliminary studies suggest an important role for macrophage colony-stimulating factor (m-CSF), transforming growth factor (TGF)-beta1, matrix metalloproteases (MMPs), and tissue inhibitors of metalloproteases (TIMPs) in regulating inflammatory and fibrotic events in the conjunctiva of OCP patients, and in fibroblasts isolated from conjunctiva of OCP patients. In our proposed study, we will determine the role of macrophage-recruiting molecules, isoforms of TGF-beta, connective tissue growth factor (CTFG), specific members of MMPs and TIMPs (as determined by our microarray analysis) in conjunctiva of patients with OCP. We will perform in vivo studies using an established mouse model of conjunctival scarring to determine the effects of blocking CTGF in this model. We anticipate that the results from studies proposed in this grant application will provide information that will identify and describe some of the key molecules that influence conjunctival scarring in patients with OCP. The studies have significant therapeutic potential. The identified molecules or portion of processes that mediate could be blocked or arrested, and this may result in cessation of disease progression and, prevention of blindness.
| Malik, Mohsin; Gurcan, Hakan M; Christen, William et al. (2007) Relationship between cancer and oral pemphigoid patients with antibodies to alpha6-integrin. J Oral Pathol Med 36:1-5 |
| Rashid, Khwaja Aftab; Stern, Joel N H; Ahmed, A Razzaque (2006) Identification of an epitope within human integrin alpha 6 subunit for the binding of autoantibody and its role in basement membrane separation in oral pemphigoid. J Immunol 176:1968-77 |
| Razzaque, Mohammed S; Foster, C Stephen; Ahmed, A Razzaque (2004) Role of macrophage migration inhibitory factor in conjunctival pathology in ocular cicatricial pemphigoid. Invest Ophthalmol Vis Sci 45:1174-81 |
