2013 — 2015 |
Thompson-Peer, Katherine Louise |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Identification of Axon and Dendrite Regeneration Antagonists in Drosophila @ University of California, San Francisco
DESCRIPTION (provided by applicant): Damage to the central nervous system is devastating and debilitating. There are no effective clinical treatments for serious central nervous system damage. Paralysis affects ~5.5 million Americans, according to a study in 2008 (Reeve Foundation, One Degree of Separation). Research into why neurons can't regrow across injury sites has yielded some insight. Yet the regeneration-preventing factors identified thus far only explain a small part of why there is no recovery. To develop effective therapies, we need a more comprehensive understanding of extrinsic and intrinsic regeneration antagonists. Our lab has recently developed a system that uses a two-photon laser to cut either the axon or dendrite projections of neurons in flies. After injury, we observe the degeneration of these projections and any subsequent regeneration. Regeneration in the dendritic arborization (da) neurons in flies shares a number of important characteristics with regeneration in mammalian systems, and allows unbiased discovery of genes that influence this process. I aim to use this system to ask fundamental questions about axonal and dendritic regeneration. (1) What are the intrinsic differences that allow some neurons to have the capacity to regenerate when other cells do not, even in the same permissive environment? Similar classes of well-described da neurons show distinct regenerative capacities. We know transcription factors that define the characteristics of these cell types, including the pattern of dendritic arborization, axonal targeting, and receptor expression. Do these transcription factors also define regenerative ability differences, and by what mechanism? (2) How do external cues from glial cells regulate whether axon regeneration occurs? Glial cells engulf neurite fragments during degeneration after damage. We will characterize the role of glia in regeneration, and examine glial signals that may regulate whether a substrate is permissive for axon growth. To what extent do signals inside the neuron and in the surrounding tissue combine to regulate regeneration? (3) What novel antagonists of regeneration can we identify and validate? After screening for novel regulators of regeneration, we will investigate whether identified antagonists are components of known or unique pathways. With answers to these questions, we will be able to better explain why neuron regeneration fails and more effectively design ways to treat injury. My graduate experience provides a solid foundation for examining the nervous system using genetics and imaging, and the experiments proposed here represent significant opportunities for personal training and discovery in a stimulating and supportive environment.
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2016 — 2021 |
Thompson-Peer, Katherine Louise |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Mechanisms of Dendrite Regeneration After Injury @ University of California, San Francisco
At the most straightforward level, a neuron receives information along dendrites, and sends information down an axon to synaptic contacts. Dendrites are injured by traumatic brain injury, stroke, and many forms of neurodegeneration, yet while factors that control axon regeneration after injury have been extensively studied, we know almost nothing about dendrite regeneration. My long term research goal is to understand the cellular mechanisms of dendrite regeneration after injury. During my graduate training with Dr Joshua Kaplan at Harvard, I used quantitative imaging, behavior, and C. elegans genetics to examine a key step in neuronal circuit development. For my postdoctoral training with Dr Yuh Nung Jan at UCSF, I have transitioned to studying the response to neurons to dendrite injury in Drosophila. I have found that the da sensory neurons in the Drosophila peripheral nervous system exhibit robust regeneration of dendrites after injury and am using this system to explore fundamental features of dendrite regeneration. I have observed that regenerated dendrites are identical to uninjured dendrites in many ways, like the trafficking of sensory ion channels and the expression of cell-type specific transcription factors. However the morphology and patterning of injury-induced dendrites are significantly defective compared to uninjured dendrites. Moreover, manipulations that alter the excitability of neurons specifically alter the regrowth of neurons after injury without affecting uninjured neurons, suggesting that dendrite regeneration is an activity-dependent process. I propose that developing a research program to deepen our knowledge about dendrite regeneration will create a new framework for understanding how neurons recover from injury. My short term research goals for the K99 mentored phase are to gain additional experimental skills to test the function of regenerated dendrites. These skills will facilitate the research proposed here: to investigate the activity dependence of dendrite regeneration; to examine the cell biological changes that underlie the alterations in regenerated dendrite morphology and their functional consequences; and explore the relationship between dendrite arbor maintenance and dendrite regeneration after injury. The proposed experimental training and the planned career development activities will prepare me to transition to leading an independent and productive research program as a tenure-track faculty member at a research institution.
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