Critical differences in responses to stress exist between the central (CNS) and peripheral nervous systems (PNS). In contrast to the CNS, where sustained cellular perturbation, such as that due to accumulated amyloid- beta peptide (Abeta), leads to eventual neuronal loss, in the peripheral nervous system, an appropriately limited inflammatory response effectively promotes neuronal regeneration after injury, in the peripheral nervous system, an appropriately-limited inflammatory response effectively promotes neuronal regeneration after injury. An initial inflammatory response in segments distal to the injured nerve provides an environment for axonal regeneration. Monocyte-derived macrophages promote removal of damaged myelin sheaths and elaborate key mediators which redirect Schwann cell and neuronal function from homeostatic myelination and transmission modes, to proliferative/non-myelinating and growth phenotypes, respectively. Recent findings have implicated ligands of the receptor RAGE in macrophage recruitment and activation, and neurite outgrowth and extension. EN-RAGEs (Extracellular Newly- identified RAGE binding proteins), members of the S100/calgranulin family synthesized and/or released by damaged Schwann cells, interact with RAGE to stimulate macrophage chemotaxis and activation. EN- RAGEs may also mediate neurite outgrowth via engagement of neuronal chemotaxis and activation. EN-RAGEs may also mediate neurite outgrowth via engagement of neuronal RAGE, a function shared with amphoterin, another RAGE ligand. Our pilot studies display the proximity of these mediators and RAGE-bearing cells in injured peripheral nerve, and upon unilateral crush of the sciatic nerve in mice, administration of blocking F(ab')s derived from anti-RAGE, anti-EN- RAGE or anti-amphoterin IgG, but not non-immune (Fab') s, impairs removal of myelin and diminishes regeneration. We hypothesize that rapid release of EN-RAGEs by perturbed Schwann cells triggers RAGE- dependent macrophage recruitment and activation critical to initiation of reparative mechanisms. Subsequently, EN-RAGEs and amphoterin target neuronal RAGE thereby promoting axonal growth into approximately prepared distal nerve stumps. We speculate that these processes are suppressed in aged mice. The goal of Project 2 is to dissect the role of RAGE in peripheral nerve injury utilizing novel transgenic models with targeted expression of a dominant-negative RAGE, a form of the receptor lacking the cytosolic tail which blocks RAGE signaling, in macrophages and/or neurons. Project 2 will work closely with Project 1, and will obtain technical assistance from Core B. Collaborative interactions include: exchange of reagents regarding RAGE biology (Project 1), evaluation of cellular stress (Projects 1, 3, and 4), and mouse breeding (Core B).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
3P01AG017490-02S1
Application #
6493033
Study Section
Special Emphasis Panel (ZAG1)
Project Start
2001-09-01
Project End
2002-08-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Juranek, Judyta K; Daffu, Gurdip K; Geddis, Matthew S et al. (2016) Soluble RAGE Treatment Delays Progression of Amyotrophic Lateral Sclerosis in SOD1 Mice. Front Cell Neurosci 10:117
Carlson, Emily A; Marquez, Rebecca T; Du, Fang et al. (2015) Overexpression of 17?-hydroxysteroid dehydrogenase type 10 increases pheochromocytoma cell growth and resistance to cell death. BMC Cancer 15:166
Du, Heng; Guo, Lan; Wu, Xiaoping et al. (2014) Cyclophilin D deficiency rescues A?-impaired PKA/CREB signaling and alleviates synaptic degeneration. Biochim Biophys Acta 1842:2517-27
Juranek, Judyta K; Geddis, Matthew S; Rosario, Rosa et al. (2013) Impaired slow axonal transport in diabetic peripheral nerve is independent of RAGE. Eur J Neurosci 38:3159-68
Borger, Eva; Aitken, Laura; Du, Heng et al. (2013) Is amyloid binding alcohol dehydrogenase a drug target for treating Alzheimer's disease? Curr Alzheimer Res 10:21-9
Juranek, Judyta K; Geddis, Matthew S; Song, Fei et al. (2013) RAGE deficiency improves postinjury sciatic nerve regeneration in type 1 diabetic mice. Diabetes 62:931-43
Fang, Fang; Chen, Xiaochun; Huang, Tianwen et al. (2012) Multi-faced neuroprotective effects of Ginsenoside Rg1 in an Alzheimer mouse model. Biochim Biophys Acta 1822:286-92
Du, Heng; Guo, Lan; Yan, Shirley ShiDu (2012) Synaptic mitochondrial pathology in Alzheimer's disease. Antioxid Redox Signal 16:1467-75
Huang, Tianwen; Fang, Fang; Chen, Limin et al. (2012) Ginsenoside Rg1 attenuates oligomeric A?(1-42)-induced mitochondrial dysfunction. Curr Alzheimer Res 9:388-95
Carnevale, Daniela; Mascio, Giada; D'Andrea, Ivana et al. (2012) Hypertension induces brain ?-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature. Hypertension 60:188-97

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