# Understanding Endoplasmic Reticulum-Mitochondrial Cross-Talk in Corneal Endothelial Cells

> **NIH NIH K99** · SCHEPENS EYE RESEARCH INSTITUTE · 2020 · $102,744

## Abstract

Project Summary
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 dedic...

## Key facts

- **NIH application ID:** 9949000
- **Project number:** 1K99EY031339-01
- **Recipient organization:** SCHEPENS EYE RESEARCH INSTITUTE
- **Principal Investigator:** Varun Kumar
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $102,744
- **Award type:** 1
- **Project period:** 2020-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949000

## Citation

> US National Institutes of Health, RePORTER application 9949000, Understanding Endoplasmic Reticulum-Mitochondrial Cross-Talk in Corneal Endothelial Cells (1K99EY031339-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9949000. Licensed CC0.

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