James L. Franklin, Ph.D. Associate Professor Pharmaceutical and Biomedical Sciences Office: Room 357, R.C. Wilson Pharmacy Phone: (706) 542-5399 E-mail: jfrankli@rx.uga.edu

Biosketch

B.S. Zoology	North Carolina State University	Raleigh, NC	1976
Ph.D. Physiology	University of North Carolina Chapel Hill	Chapel Hill, NC	1990
Postdoctoral Fellow	Washington University School of Medicine	St. Louis, MO	1990-1997
Assistant Professor	University of Wisconsin Medical School	Madison, WI	1997-2004
Assistant Professor	University of Georgia	Athens, GA	2004-2007
Associate Professor	University of Georgia College of Pharmacy	Athens, GA	2007-Present

Honors and Awards
National Institutes of Health Grant “Free Radicals and Mitochondria in Neuronal Apoptosis,” 1998-2007
Guest Editor of “Antioxidants and Redox Signaling,” 2003
Nominated as a candidate for Reynolds Chair in Developmental Neuroscience, Wake Forest University, 2002
Site Visit Reviewer for National Institutes of Health, 2002
Graduate School Research Award, University of Wisconsin Madison, 2000
National Institutes of Health Infrastructure Award, 1999-2000
Howard Hughes Faculty Development Award, University of Wisconsin Madison, 1997-1999
Service on National Institutes of Health MDCN2 Study Section, 1998

Research Interests
The research in our laboratory focuses on understanding cellular mechanisms of neuronal apoptosis and the molecular signaling pathways by which neurotrophins and other agents promote neuronal survival. Apoptosis is a well-characterized, active form of death in which a cell participates in its own demise. As much as fifty percent of neurons produced during embryogenesis die by apoptosis shortly before birth or soon thereafter. This large-scale self-destruction acts to sculpt the developing nervous system. Availability of a sufficient quantity of a required neurotrophic factor provided by target, or other, tissues determines whether a neuron will survive or undergo apoptotic death during this developmental period. While apoptosis serves a physiologically-appropriate function during neuronal development, it also contributes to the death of neurons in stroke, neurodegenerative diseases, and many other neuropathological conditions. Therefore, elucidating the mechanisms of neuronal cell death is important for understanding both the basic biology of developmental death in the nervous system and death occurring in pathological states. Such an understanding may lead to therapeutic interventions for neuropathologies, few of which can be treated effectively at the present time.

We use several peripheral and central nervous system models to investigate cellular mechanisms underlying neuronal apoptosis. Our primary model consists of embryonic rat or mouse sympathetic neurons in cell culture. These neurons die by apoptosis, either in vivo or in vitro, when deprived of their required neurotrophic factor, nerve growth factor (NGF). The molecular event directly responsible for killing the cells is degradation of cellular substrates by caspase family proteases. Central to this process is release of cytochrome c from mitochondria into the cytoplasm where it binds onto the protein apoptosis protease activating factor-1 (Apaf-1) forming an Apaf-1/cytochrome c complex that triggers caspase activity. Our principal interest is to understand the mechanism underlying cytochrome c release from mitochondria. In the sympathetic cell culture model of apoptosis, this release does not occur until 18-30 hours after NGF removal. We have found that mitochondria greatly increase production of free radical oxygen (reactive oxygen species; ROS) many hours prior to this time. This ROS burst appears to directly contribute to cytochrome c release. We are focusing on understanding the mechanisms underlying this burst, including how NGF regulates the burst and how ROS contribute to cytochrome c release. Our evidence suggests that the increased ROS is caused by binding of the pro-apoptotic member of the Bcl-2 family of proteins, Bax, with mitochondria. We are currently starting a new project aimed at extending our findings in sympathetic neurons to a model of Parkinsonism, a neurodegenerative disease thought to involve both ROS and Bax. We use transgenic and knockout mice and a wide variety of molecular, pharmacological, biochemical, and imaging methods in these studies. Our lab is well-funded by the National Institutes of Health.

Representative Publications
Kirkland, R.A. and Franklin, J.L. Bax affects production of reactive oxygen by the mitochondria of non-apoptotic neurons. Experimental Neurology 2007 204: 458-461.

Kirkland, R.A. and Franklin, J.L. Rate of neurite outgrowth in sympathetic neurons is highly resistant to suppression of protein synthesis:Role of protein degradation/synthesis coupling. Neuroscience Letters 2007 411: 52-55.

Kirkland, R.A. and Franklin, J.L. Pro-oxidant effects of NGF withdrawal and MEK inhibition in sympathetic neurons. Antioxidants and Redox Signaling 2003, 5: 635–639.

Kirkland, R.A., Windelborn, J.A., Kasprzak, J.M., and Franklin, J.L. A Bax-induced pro-oxidant state is critical for cytochrome c release in programmed neuronal death. Journal of Neuroscience 2002, 22: 6480–6490.

Kirkland, R.A., Rao, A.M., Hatcher, J.F., and Franklin, J.L. Loss of cardiolipin and mitochondria during programmed neuronal death: evidence of a role for lipid peroxidation and autophagy. Neuroscience 2002, 115: 587–602.

Kirkland, R.A., and Franklin, J.L. Evidence for redox regulation of cytochrome c release during programmed neuronal death: antioxidant effects of protein synthesis and caspase inhibition. Journal of Neuroscience 2001, 21: 1949–1963.