Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disorder with an incidence of 1:3500. NF1 is associated with mutations in the NF1 gene and characterized by learning impairment, abnormal growth of neural crest derivatives such as Schwann cells and melanocytes and, most prominently, develop tumors. Multiple neurofibromas are the defining feature of NF1 and they are the cause for much of the medical burden of this condition. The major cellular component of neurofibromas are Schwann cells. Schwann cells derived from neurofibromas are angiogenic and invasive as are Schwann cells from NF1-/- and +/- knockout mice indicating that tumor cells produce altered levels of growth factors. It is not known, which growth factors are upregulated as a result of NF1 deficiency. Recent work from the principal investigator's laboratory has identified a number of growth factors which are upregulated in NF1-/- Schwann cells. These studies have shown that one of these factors, midkine (MK), stimulates proliferation of systemic and brain endothelial cells and of neurofibroma derived cells. MK is able to induce tumor growth after transfection into non-tumorigenic, MK negative SW-13 cells and NIH3T3 cells. Furthermore, the principal investigator found MK expressed in Schwann cells and endothelial cells of dermal neurofibromas, and in malignant and benign peripheral nerve sheet tumors (PNST) of NF1 patients. Finally, MK is expressed in the skin of NF1 patients but is not expressed in non-NF1 skin. The principal investigator proposes experiments that will elucidate the physiological role of MK and its contribution to tumor growth.
In Aim 1 he will express MK in neurofibroma-derived cell lines which have a low tumorigenic potential and express very low levels of MK and study phenotypic changes. The expression of MK will be under the control of a tetracycline-regulatable promoter that allows to regulate transfected MK in vitro and in vivo by administration of tetracycline.
In Aim 2 he will use molecular targeting of MK mRNA with ribosomes to elucidate the contribution of MK to tumor growth of malignant PNST-derived cells that express high levels of MK.
In Aim 3 he will study tumor formation in NF1+/- MK-/- double knockout mice. Neurofibromas will be induced in these mice by nerve transection and tumor incidence, time of onset and tumor growth rate will be evaluated.
In Aim 4 he proposes to study whether MK levels can be detected in skin and/or serum samples of NF1 patients and may serve as a diagnostic indicator for NF1.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Special Emphasis Panel (ZRG1-NLS-3 (01))
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Finkelstein, Robert
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Massachusetts General Hospital
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Mashour, George A; Drissel, Stephanie N; Frahm, Silke et al. (2005) Differential modulation of malignant peripheral nerve sheath tumor growth by omega-3 and omega-6 fatty acids. Oncogene 24:2367-74
Mashour, George A; Driever, Pablo Hernaiz; Hartmann, Melanie et al. (2004) Circulating growth factor levels are associated with tumorigenesis in neurofibromatosis type 1. Clin Cancer Res 10:5677-83
Kurtz, Andreas; Martuza, Robert L (2002) Antiangiogenesis in neurofibromatosis 1. J Child Neurol 17:578-84; discussion 602-4, 646-5
Mashour, G A; Ratner, N; Khan, G A et al. (2001) The angiogenic factor midkine is aberrantly expressed in NF1-deficient Schwann cells and is a mitogen for neurofibroma-derived cells. Oncogene 20:97-105
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