Axon degeneration contributes to the pathologies of diabetes, glaucoma, and Parkinson's Disease, and is the dose-limiting side effect of chemotherapeutic treatments. It is an actively regulated program similar to apoptosis but distinct in its execution mechanisms. Cellular programs controlling the preservation and destruction of axons are not well understood, and we do not currently have therapies to prevent such degeneration. Development of therapies to treat or prevent axon degeneration could significantly improve the quality of life for patients with the above disorders while also reducing the burden they place on our health care system. Two genes are currently known to influence axon degeneration in neurons: Wlds, and the MAP kinase DLK. Inhibition of DLK or its downstream kinase JNK significantly delay axon degeneration in injury models. I propose to investigate the cellular mechanisms controlled by DLK that allow this delay. I will culture primary somatosensory neurons in vitro, injure axons in culture, and use cellular assays, confocal microscopy, and biochemistry to ask how DLK regulates microtubules, axon transport, and other pathways affected by axon degeneration. The intersection of the DLK and Wlds pathways will also be examined, as these two control mechanisms may act in an additive manner and could provide additional insight into designing molecular therapies for axon degeneration. For this aim we will use already established transgenic mice and lentiviral infection of neurons in vitro and in vivo. Finally, I will test whether DLK or JNK inhibition control degeneration in axons of retinal ganglion cells (RGCs) comprising the optic nerve, as these axons undergo degeneration during glaucoma. Both in vitro studies of RGCs and in vivo injury models, as well as established mouse models of glaucoma, will be used to ask whether DLK and/or Wlds exert protective effects in this system and whether DLK pathway inhibition may be an appropriate therapeutic strategy for glaucoma. Understanding axon degeneration will have significant public health benefits due to the broad spectrum of diseases where axon degeneration causes symptoms. Our research seeks to determine effective avenues for delay or prevention of axon degeneration that could be used in clinical settings

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS065615-02
Application #
7922591
Study Section
Special Emphasis Panel (ZRG1-F03A-F (20))
Program Officer
Kleitman, Naomi
Project Start
2009-06-19
Project End
2011-09-18
Budget Start
2010-06-19
Budget End
2011-06-18
Support Year
2
Fiscal Year
2010
Total Cost
$50,474
Indirect Cost
Name
Washington University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Bhattacharya, Martha R C; Gerdts, Josiah; Naylor, Sarah A et al. (2012) A model of toxic neuropathy in Drosophila reveals a role for MORN4 in promoting axonal degeneration. J Neurosci 32:5054-61