MITOCHONDRIAL MECHANISMS IN OPTIC NEUROPATHY

Project: Research project

Description

The broad, long-term objective of this project is to determine the pathophysiological mechanism of Leber's Hereditary Optic Neuropathy (LHON), in the hopes that a mechanistic understanding of this disease will lead to more effective therapy. LHON is the result of the inheritance of primary mutations of the mtDNA in three different subunits of Complex I of the mitochondrial respiratory chain. We have recently demonstrated that the most common LHON pathogenic mutation can be transferred into human Nt2 cells and are differentiable into neuron-like cells. We have also observed in earlier work that LHON cells appear to be activated for apoptosis. Thus there are six Specific Aims: 1) to construct all three LHON mutations in a cell environment differentiable into neurons, and measure the effects of differentiation, of respiratory substrates, and of induction of electron transport chain activity on viability in the neuronal environment; 2) to measure the bioenergetic effects of differentiation into a neuronal environment in cells and mitochondria, by mitochondrial membrane potential, oxygen consumption, and reduction of Alamar blue; 3) To measure the apoptotic activity of Nt2 cells and neurons bearing the LHON mutations, and to determine if a particular step in this pathway is activated in LHON cells; 4) to determine if neuron-specific excitotoxic mechanisms are activated in LHON neurons; 5) to determine if LHON mutations exert a concerted effect on gene expression, by array analysis of mRNA levels in mutant and control neurons, and 6) based on the results of Aims 1-5, to integrate and confirm the understanding of the LHON pathophysiological mechanism by rescue with mechanism-specific pharmacological agents, including bioenergetic supplements, anti- apoptotic agents, glutamate antagonists, antioxidants and chelators.
StatusFinished
Effective start/end date5/1/006/30/17

Funding

  • National Institutes of Health: $353,286.00
  • National Institutes of Health: $23,395.00
  • National Institutes of Health: $41,052.00
  • National Institutes of Health: $448,373.00
  • National Institutes of Health: $377,300.00
  • National Institutes of Health: $371,250.00
  • National Institutes of Health: $439,257.00
  • National Institutes of Health: $258,777.00
  • National Institutes of Health: $385,000.00
  • National Institutes of Health: $406,450.00
  • National Institutes of Health: $408,634.00
  • National Institutes of Health: $259,729.00
  • National Institutes of Health: $365,750.00
  • National Institutes of Health: $258,563.00
  • National Institutes of Health: $259,875.00
  • National Institutes of Health: $62,925.00
  • National Institutes of Health: $359,125.00

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Optic Nerve Diseases
Leber's Hereditary Optic Atrophy
Autosomal Dominant Optic Atrophy
Retinal Ganglion Cells
Cell Death
Animal Disease Models
Animal Models
Mutation
Neurons
Drug Repositioning
High-Throughput Screening Assays
Mitochondrial Diseases
Organized Financing

ASJC

  • Medicine(all)