Long-term objectives of the current proposal are to discover the fundamental causes and etiologic factors responsible for uveitis as well as to find a cure for this disease, which is responsible for over 2.8% of blindness in the United States. A recent report from the Northern California Epidemiology Study suggested a higher disease rate for the older population in US. Unfortunately, treatment options available to uveitis patients have limitations because currently uveitis is treated symptomatically only. Therefore, continuous efforts and future investigations are needed so that uveitis could be prevented and efficient and safe therapies for future could be developed. Idiopathic anterior uveitis (AU) is the most common form of intraocular inflammation in humans and the recurrent nature of the disease can lead to permanent visual loss. Experimental autoimmune anterior uveitis (EAAU) is an organ specific autoimmune disease of the eye which serves as an animal model of idiopathic human AU. Recent studies from the Principal Investigator's (PI) laboratory have identified a critical role of complement and complement regulatory proteins (CRegs) in the pathogenesis of idiopathic AU using EAAU animal model. In the current proposal the PI proposes to investigate the underlying mechanisms by which alternative pathway (AP) of complement activation plays a crucial role in the development of EAAU so that novel therapeutic targets based on selective blockade of AP could be identified. Therapeutic potential of selective blockade of complement derived inflammatory mediators such as C3a, C5a, iC3b and membrane attack complex (MAC) in the treatment of EAAU will also be explored in the current application. Finally, the PI intends to determine the importance of cross-talk between complement and immune cells in the pathogenesis of EAAU.
The specific aims of this proposal are: 1. To investigate the underlying mechanisms by which alternative pathway (AP) of complement activation plays a crucial role in the development of idiopathic anterior uveitis using experimental autoimmune anterior uveitis (EAAU) animal model. 2. To explore the role of complement activation products - C3a, C5a, iC3b and membrane attack complex (MAC) in the pathogenesis of idiopathic anterior uveitis. 3. To determine the role of cross-talk between complement and immune cells in the pathogenesis of EAAU - Modulation of immune cell function by C3, the third component of complement in draining lymph nodes. The proposed studies are particularly germane because they provide potential tools to fully understand the role of complement in the pathogenesis of idiopathic AU. Furthermore, these studies are required for the development of novel effective therapeutic strategies based on selective modulation of complement system.
The results derived from the proposed study may lead to more effective management and/or treatment of human idiopathic anterior uveitis. In future, complement inhibitors might be used as novel antiuveitic agents in the clinic for the treatment of this important form of human ocular disease.
|Liu, Juan; Jha, Purushottam; Lyzogubov, Valeriy V et al. (2011) Relationship between complement membrane attack complex, chemokine (C-C motif) ligand 2 (CCL2) and vascular endothelial growth factor in mouse model of laser-induced choroidal neovascularization. J Biol Chem 286:20991-1001|
|Manickam, Balasubramanian; Jha, Purushottam; Matta, Bharati et al. (2011) Inhibition of complement alternative pathway suppresses experimental autoimmune anterior uveitis by modulating T cell responses. J Biol Chem 286:8472-80|
|Manickam, Balasubramanian; Jha, Purushottam; Hepburn, Natalie J et al. (2010) Suppression of complement activation by recombinant Crry inhibits experimental autoimmune anterior uveitis (EAAU). Mol Immunol 48:231-9|
|Bora, Nalini S; Jha, Purushottam; Lyzogubov, Valeriy V et al. (2010) Recombinant membrane-targeted form of CD59 inhibits the growth of choroidal neovascular complex in mice. J Biol Chem 285:33826-33|