Therapeutic approaches for neurodegenerative and neural injury conditions aim to reconnect neural circuits through the regeneration of damaged axons. Most neurodegenerative conditions strike after neural development has concluded, and many, including Alzheimer's, Huntington's, and Parkinson's diseases, have been found to involve mitochondria. Mitochondria produce energy required for cellular function, and their specific roles in neurons, which consume large amounts of energy, are unclear. The purpose of this proposal is to investigate the mechanism of mitochondrial involvement in axon regeneration, particularly in the context of the genetic interaction of mitochondria with the intracellular signaling protein PI3 kinase (PI3K). Neurons of the mammalian central nervous system fail to regenerate their axons, while neurons of the peripheral nervous system regenerate well. However, to systematically study the basic molecular mechanisms of axon regeneration, one needs a model organism that 1) has a reliable, accessible, and relatively limited nervous system to eliminate potentially confounding variations between neural subtype;2) has neurons that regenerate reliably;3) is amenable to tools for specifically labeling and manipulating mitochondria in intact animals;4) enables the resolution of individual axons in intact animals;5) allows the examination of multiple genetic mutants in a time- and cost-efficient manner;and 6) contains genes which are orthologous to human genes. For these reasons I have chosen to use the nematode C. elegans as an experimental model to study mitochondria in axon regeneration. I have made the initial observation that the worm PI3K ortholog age-1 genetically interacts with the mitochondrial ubiquinone synthase gene clk-1/COQ7, in that mutations in each gene individually diminish regeneration of the PLM mechanosensory neuron axon in adulthood, but when combined the mutations cancel each other out to restore regeneration to normal levels. I will gain training in working with C. elegans and in the topics of axon regeneration and mitochondria through the following specific aims:
Aim 1 : Determine the cellular action of the age-1/PI3K and clk-1/COQ7 interaction in regeneration, and Aim 2: Determine the mechanism by which age-1/PI3K regulates mitochondrial state. I will use genetics, microscopy, laser axotomy, live imaging, and genetic reporters of intracellular signaling chemicals to carry out the study. The completion of this proposal will provide a deeper understanding of the actions of mitochondria in regenerating axons and will define a novel role of interaction of PI3K with mitochondria. These insights will have implications for future therapeutic strategies targeting axon regeneration in neurodegenerative diseases in which mitochondria are mechanistically implicated, such as Alzheimer's, Huntington's, and Parkinson's diseases.

Public Health Relevance

The aim of this research is to understand the biology of regenerating neurons for treatment of neurodegenerative diseases, such as Parkinson's, Alzheimer's, and Huntington's diseases, which most often affect adults. Many neurodegenerative diseases are characterized by dysfunctional mitochondria, the units within cells which produce energy, which also decline in function with normal aging. Understanding the role of mitochondria in energy-hungry neurons and how they interact with other cellular processes during regeneration will help us develop better therapeutic strategies for adult patients of neurodegenerative diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Jakeman, Lyn B
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University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
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