The primary goal of this project is to test the hypothesis that retina is a target tissue for iron overload and iron-induced oxidative damage in hereditary hemochromatosis (HHC), the most prevalent genetic disease characterized by iron accumulation in systemic organs. Mutations in HFE [Histocompatability leukocyte antigen class I-like protein involved in iron (FE) homeostasis], a gene coding for a cell surface protein involved in the regulation of iron homeostasis, are responsible for ~85% cases of this disease (classical HHC). The remaining cases arise from mutations in four other genes (hemojuvelin, hepcidin, transferrin receptor 2, and ferroportin), also coding for iron-regulatory proteins. Mutations in hemojuvelin (HJV) cause juvenile HHC in which excessive iron accumulation occurs in organs at a much younger age than in classical HHC. Surprisingly, little is known on whether retina is affected in this disease. We have shown for the first time that all five HHC-associated genes are expressed in the retina: Hfe exclusively in RPE;Hjv in RPE and neural retina;hepcidin and ferroportin in RPE, Muller cells, and photoreceptor cells;and transferrin receptor 2 throughout the retina. More importantly, we have evidence for age-dependent morphological changes in the retina in a mouse model of classical HHC (Hfe-/- mouse). In addition, we found that Hfe-/- RPE cells exhibit a hyperproliferative phenotype compared to wild type RPE cells. These findings are novel and point to an interesting link between iron status and cell proliferation. Our studies also show that the expression of Hfe, Hjv, and hepcidin is markedly altered in RPE and in retina as a result of infection with cytomegalovirus (CMV) and herpes simplex virus-1 (HSV1). These interesting and important findings form the basis for the proposed studies.
Aim 1 is to test the hypothesis that HHC is associated with iron overload in RPE and retina with functional consequences. This will be tested using two different mouse models, one representing the classical HHC (Hfe-/- mouse) and the other representing the juvenile HHC (Hjv-/- mouse).
Aim 2 is to test the hypothesis that deletion of HFE and HJV has consequences that go far beyond iron accumulation and associated oxidative damage. Studies under this specific aim will include examination of the molecular events responsible for the hyperproliferative phenotype of Hfe-/- RPE cells as well as for the epithelial-to-mesenchymal transition in Hjv-/- RPE cells and for the disruption of BMP signaling and its consequences in Hjv-/- retina.
Aim 3 is to test the hypothesis that infection of RPE and retina with CMV and HSV1 disrupts iron homeostasis by modulating the expression of iron-regulatory genes. This will be investigated using primary cultures of retinal cells in vitro and with wild type and HHC mouse models in vivo. These studies will provide important insight into the molecular mechanisms involved in the maintenance of iron homeostasis in the retina in health and disease and on the involvement of the retina in HHC, the most prevalent genetic disease in Caucasians.
Hereditary hemochromatosis (HHC) is the most prevalent genetic disease characterized by excessive iron accumulation in various systemic organs, but whether the iron status in the retina is affected in this disease is not known. It is known however, that excessive iron accumulation in the retina causes oxidative damage and retinal degeneration. Studies proposed in this project will investigate the HHC-associated changes in the iron status, structure, and morphology of the retina and the functional consequences using transgenic mouse models of HHC, and assess the involvement of various iron-regulatory proteins in RPE and the retina during infection with cytomegalovirus and herpes simplex virus-1.
|Arjunan, Pachiappan; Gnanaprakasam, Jaya P; Ananth, Sudha et al. (2016) Increased Retinal Expression of the Pro-Angiogenic Receptor GPR91 via BMP6 in a Mouse Model of Juvenile Hemochromatosis. Invest Ophthalmol Vis Sci 57:1612-9|
|Tawfik, Amany; Gnana-Prakasam, Jaya P; Smith, Sylvia B et al. (2014) Deletion of hemojuvelin, an iron-regulatory protein, in mice results in abnormal angiogenesis and vasculogenesis in retina along with reactive gliosis. Invest Ophthalmol Vis Sci 55:3616-25|
|Gnana-Prakasam, Jaya P; Baldowski, Renee B; Ananth, Sudha et al. (2014) Retinal expression of the serine protease matriptase-2 (Tmprss6) and its role in retinal iron homeostasis. Mol Vis 20:561-74|
|Ananth, Sudha; Gnana-Prakasam, Jaya P; Bhutia, Yangzom D et al. (2014) Regulation of the cholesterol efflux transporters ABCA1 and ABCG1 in retina in hemochromatosis and by the endogenous siderophore 2,5-dihydroxybenzoic acid. Biochim Biophys Acta 1842:603-12|
|Gnana-Prakasam, Jaya P; Veeranan-Karmegam, Rajalakshmi; Coothankandaswamy, Veena et al. (2013) Loss of Hfe leads to progression of tumor phenotype in primary retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 54:63-71|
|Sreekumar, Parameswaran G; Chothe, Paresh; Sharma, Krishna K et al. (2013) Antiapoptotic properties of ?-crystallin-derived peptide chaperones and characterization of their uptake transporters in human RPE cells. Invest Ophthalmol Vis Sci 54:2787-98|
|Bozard, B Renee; Chothe, Paresh P; Tawfik, Amany et al. (2012) Regulation of proton-coupled folate transporter in retinal Müller cells by the antipsoriatic drug monomethylfumarate. Glia 60:333-42|
|Ananth, Sudha; Thakkar, Santoshanand V; Gnana-Prakasam, Jaya P et al. (2012) Transport of the synthetic opioid peptide DADLE ([D-Ala2,D-Leu5]-enkephalin) in neuronal cells. J Pharm Sci 101:154-63|
|Gnana-Prakasam, Jaya P; Tawfik, Amany; Romej, Michelle et al. (2012) Iron-mediated retinal degeneration in haemojuvelin-knockout mice. Biochem J 441:599-608|
|Gnana-Prakasam, Jaya P; Ananth, Sudha; Prasad, Puttur D et al. (2011) Expression and iron-dependent regulation of succinate receptor GPR91 in retinal pigment epithelium. Invest Ophthalmol Vis Sci 52:3751-8|
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