Candidate: The candidate is a MD/PhD-trained clinician-scientist and board-eligible ophthalmologist currently completing a neuro-ophthalmology fellowship, who will be promoted to Duke Eye Center faculty in July, 2017. His research interest relates to pathobiology and drug discovery in mitochondrial optic neuropathies, a class of blinding disease for which effective therapy does not currently exist. Career Development Plan: The candidate proposes to create a mouse model of retinal ganglion cell (RGC)-specific complex I deficiency, predicted to cause particularly rapid and severe RGC degeneration. The proposed research will allow the candidate to gain experience in animal modeling of human disease, biochemical and histological assays of mitochondrial dysfunction, and retinal electrophysiology. Animal models, reagents, and insights developed in this project will serve as the basis for an R01 proposal to be submitted by the candidate in his final year of K08 support. Specific didactic courses in neurobiology, drug discovery and translation, toxicology, and biostatistics, as well as departmental research seminars and advanced training in responsible conduct of research will be obtained during his K08 tenure, and the candidate will present his findings regularly at national meetings and submit his work for publication. Environment: The candidate?s mentoring team consists of accomplished faculty whose wide range of expertise will be utilized in specific components of the research plan. He will also benefit from informal mentorship and interactions with world-class clinical and research faculty in the Duke Eye Center and from immersion in the dynamic intellectual environment and career development resources available throughout the university. Significant departmental commitment and deep personal investment by the mentoring team will ensure that the candidate is well positioned to transition to an independent R01-funded investigator. Research: Mitochondrial dysfunction frequently results in vision loss from optic neuropathy that reflects the particular sensitivity of RGCs to impaired aerobic metabolism and increased oxidative stress. This application?s central hypotheses are that (1) mitochondria-related RGC degeneration is a cell-autonomous process and (2) RGC metabolism may therefore be manipulated to make these cells less susceptible to mitochondrial insults.
Aim 1 will test the first hypothesis by creating a mouse with severe deficiency of mitochondrial complex I specifically in RGCs via conditional knockout of the subunit ndufs4. RGCs in these mice will be assessed for histological, electrophysiological, and metabolic abnormalities.
Aim 2 tests the second hypothesis by augmenting Hif-1? signaling with complementary genetic and pharmacologic approaches and assessing whether biasing RGC metabolism toward anaerobic glycolysis makes RGCs resistant to mitochondrial dysfunction and could represent a viable therapeutic strategy.

Public Health Relevance

Mitochondrial dysfunction is an important cause of vision loss and is believed to play a mechanistic role in a number of optic neuropathies, most notably in primary mitochondrial optic neuropathies like Leber Hereditary Optic Neuropathy and Dominant Optic Atrophy, but also secondarily in more common diseases like optic neuritis, ischemic optic neuropathy, and toxic optic neuropathies. Currently there are no pharmacotherapies for mitochondrial optic neuropathies that are of more than marginal clinical benefit to affected patients. The studies proposed in this application aim to develop a better molecular understanding of the metabolic perturbations and signaling pathways leading to RGC death in mitochondrial optic neuropathies, as well as potential compensatory mechanisms that may be harnessed for therapeutic intervention in these diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08EY028610-04
Application #
10085233
Study Section
Special Emphasis Panel (ZEY1)
Program Officer
Agarwal, Neeraj
Project Start
2018-02-01
Project End
2023-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
4
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Duke University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705