Fuchs endothelial corneal dystrophy (FECD) is a common, genetically complex and age-related degenerative disease affecting approximately 4 % of the U.S.A. population with a higher incidence in females. In FECD, corneal endothelial (CE) cell loss is accompanied by extracellular matrix deposition in the form of guttae. My mentor (Ula V. Jurkunas) has reported explicitly that in FECD, oxidant-antioxidant imbalance due to suboptimum Nrf-2 regulated antioxidant defense, including a decline in its transcriptional target, NAD(P)H quinone dehydrogenase 1 (NQO1), leads to oxidative DNA damage, mitochondrial dysfunction, and apoptosis. My preliminary data also suggests the significant loss of CE in NQO1-/- mice compared to WT in the mouse model of FECD. Alike oxidative stress and mitochondrial damage, my co-mentor (Albert S. Jun) and others have implicated the role of ER stress/ Unfolded protein response (UPR) in the pathogenesis of FECD. My preliminary data also suggests the significant and earlier activation of pro-apoptotic ER stress markers for NQO-/- cell line after UVA-induced FECD model in vitro. However, there has not been any study linking ER and mitochondrial stress under oxidant-antioxidant imbalance for CE in FECD. The objective of this proposal is to define the contribution of ER stress on mitochondrial stress (altered bioenergetics and dynamics) under oxidant-antioxidant imbalance in FECD. During the mentored phase (K99) of the award, I will determine whether UVA induces ER and mitochondrial stress (Aim 1a), ER stress alters mitochondrial bioenergetic (Aim 1b) and dynamics (morphology, fragmentation, translocation) all under oxidant-antioxidant imbalance (Aim 2a). I will learn to induce and quantify ER stress with my co-mentor lab?s collaboration (Albert Jun), analyze mitochondrial bioenergetics and dynamics with mentor Ula Jurkunas and co-mentor Pere Puigserver?s lab, learn in vitro and in vivo model of FECD (Jurkunas?s lab) along with the extensive career development activities offered at Harvard Medical School. During the R00 phase, with mentor and co-mentor?s support, I will perform uncompleted parts of Aim1-2 with the additional investigation of the mechanism of ER mediated-activation of mitochondrial intrinsic apoptotic pathway (Aim 1c) via Ca+2 signaling and microtubular rearrangement (Aim 2b). Collectively, these studies will provide new insights and perspectives into the ER-Mitochondrial cross talk for corneal endothelial biology, which will advance our understanding of FECD pathogenesis. A K99 award will allow me to receive additional training in ER and Mitochondria biology along with novel training in corneal endothelial cell biology. The extensive resources and career development opportunities available at Harvard Medical School, Jurkunas, Puigserver, and Jun?s lab, as well as the research activities planned in the K99 phase, will enable me to achieve the long-term goal of becoming an independent investigator dedicated to the study of ER-Mitochondrial cross talk in corneal endothelial biology.
Fuchs Endothelial Corneal Dystrophy (FECD) is an age-related degenerative disease, the primary cause of progressive blindness from corneal endothelial cell death and the second most common cause of corneal transplants in people above 40 years old in the U.S.A. In FECD, prominent stress factors such as oxidative, ER and Mitochondria stress contribute to cell death of corneal endothelial cells, whose primary function is to maintain corneal transparency. Understanding the cross talk between these stress factors may facilitate the development of pharmacological treatments for FECD patients.