Neural injury and degeneration can arise from trauma, disease states, or normal aging and can result in impaired autonomic, sensory, motor, and/or cognitive functions. The peripheral nervous system is capable of considerable regeneration after axonal damage and, thus, offers an opportunity for studying the mechanisms underlying successful regeneration, including the identification of molecules that promote or inhibit regeneration. Our laboratory focuses on changes that occur in the region of the axotomized neuronal cell bodies at some distance from the site of an injury. Our interest is in understanding the mechanisms underlying changes after injury in three populations of cells (neurons, glial cells, and macrophages), the interrelationship of these changes, and their relevance to neural regeneration. Much of our recent research is based on the hypothesis that changes in gene expression in these three cell types are important for promoting regeneration. By microarray analysis, we have identified a large number of genes whose expression changes in sympathetic ganglia after their postganglionic nerve trunks are injured. Many of these genes had not previously been suspected to be part of the response of the nervous system to injury. In addition, some of the changes corroborate earlier findings we made using other techniques. We will examine a subset of these genes with an emphasis on (1) the functional importance of these changes for regeneration, (2) the cell types in which they occur, and (3) the molecular mechanisms underlying their induction. The genes we have chosen for study are all secreted proteins (neuropeptides, cytokines and chemokines) whose expression is substantially increased after axotomy. The central goal of this proposal is to test whether some or all of these proteins are important for successful regeneration. The demonstration of such a role for these molecules should suggest new therapeutic approaches to treating nerve damage ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
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Kleitman, Naomi
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Case Western Reserve University
Schools of Medicine
United States
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Niemi, Jon P; Filous, Angela R; DeFrancesco, Alicia et al. (2017) Injury-induced gp130 cytokine signaling in peripheral ganglia is reduced in diabetes mellitus. Exp Neurol 296:1-15
Lingappa, Jaisri R; Zigmond, Richard E (2013) Limited recovery of pineal function after regeneration of preganglionic sympathetic axons: evidence for loss of ganglionic synaptic specificity. J Neurosci 33:4867-74
Niemi, Jon P; DeFrancesco-Lisowitz, Alicia; Roldán-Hernández, Lilinete et al. (2013) A critical role for macrophages near axotomized neuronal cell bodies in stimulating nerve regeneration. J Neurosci 33:16236-48
Zigmond, Richard E (2012) Cytokines that promote nerve regeneration. Exp Neurol 238:101-6
Pellegrino, Michael J; Parrish, Diana C; Zigmond, Richard E et al. (2011) Cytokines inhibit norepinephrine transporter expression by decreasing Hand2. Mol Cell Neurosci 46:671-80
Hyatt Sachs, H; Rohrer, H; Zigmond, R E (2010) The conditioning lesion effect on sympathetic neurite outgrowth is dependent on gp130 cytokines. Exp Neurol 223:516-22
Habecker, Beth A; Sachs, Hilary Hyatt; Rohrer, Hermann et al. (2009) The dependence on gp130 cytokines of axotomy induced neuropeptide expression in adult sympathetic neurons. Dev Neurobiol 69:392-400
Sachs, Hilary H; Wynick, David; Zigmond, Richard E (2007) Galanin plays a role in the conditioning lesion effect in sensory neurons. Neuroreport 18:1729-33
Hyatt Sachs, H; Schreiber, R C; Shoemaker, S E et al. (2007) Activating transcription factor 3 induction in sympathetic neurons after axotomy: response to decreased neurotrophin availability. Neuroscience 150:887-97
Zigmond, Richard E; Vaccariello, Stacey A (2007) Activating transcription factor 3 immunoreactivity identifies small populations of axotomized neurons in rat cervical sympathetic ganglia after transection of the preganglionic cervical sympathetic trunk. Brain Res 1159:119-23

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