Kevin Victor Hackshaw

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Ohio State University
College of Medicine and Public Health
Molecular & Cellular Biochemistry
Immunology
Associate ProfessorAppointed: 1990
Professional Headshot of Kevin Victor Hackshaw

Mailing Address

William Davis Medical Research Center\480 West 9th Avenue\Room S2050
Ohio State University
Columbus, Ohio 43210
United States

Contact Information

Phone: (614) 293-4817
Fax: (614) 293-5631
Hackshaw.1@osu.edu

Qualifications

Post-Doctoral, University of Colorado Health Sciences Center, Rheumatology, 1990.
M.D., Baylor College of Medicine, Medicine, 1983.
B.Sc., Brooklyn College, City University of New York, Chemistry, 1979.

Expertise and Research Interests

My current research involves fibroblast growth factors (FGF's), which are well-described modifiers of angiogenesis, and endothelial cell proliferation. We are investigating these and other factors roles as neurotrophins in pain propagation.

From abstract:
Fibroblast growth factor-2 is a polypeptide growth factor implicated in angiogenesis, osteogenesis, wound repair and neuronal survival. FGF-2 is expressed in sites of inflammation as well as being expressed in glial cells where it acts as an inducer of NGF. However, the precise role of FGF-2 in neuropathic and inflammatory pain is still poorly understood. This proposal will improve our understanding of the signals that lead to increased FGF-2 as well as the events that are regulated by FGF-2 in the context of both neuropathic and inflammatory pain through conduction of the following specific aims.

Capsaicin treatment in adult SpNL and control rats will be used to determine the effect of C-fiber loss on FGF-2 immunoreactivity (IR) and mRNA expression and GFAP IR in spinal cord(SC) via laser capture microscopy (LCM) coupled with RT-PCR, ISH and IHC. To test if astrocyte reactivity leads or is required for increased FGF-2 expression, FGF-2 mRNA and protein levels in SC will be examined following inhibition of astrocyte reactivity in SPNL model. NGF mRNA and protein, GAP-43 (a marker of neuronal growth) and CGRP (a marker of afferent sensory fibers) IR will be examined following intrathecal (i.t.) administration of anti-FGF-2 neutralizing antibodies and/or FGF-2. The effect of inhibiting FGF-2 signaling via i.t. delivery of anti-FGF-2 neutralizing antibodies or delivery of FGF-2 will also be assessed behaviorally by assessing allodynia and hyperalgesia in the model. SC Substance P andPGE2 will be assessed by in vivo microdialysis in SpNL rats following delivery of either FGF-2 or anti-FGF-2 neutralizing antibodies. Finally, FGF-2 IR and mRNA expression will be similarly examined in the CFA model to allow us to better understand similarities and differences in signaling between these two models of chronic pain.

From Another Abstract:

Chronic pain conditions, which are estimated to affect 30% of the population in industrialized countries, are the culmination of a nociceptive cascade involving the participation of different cell types (glial cells, neurons) and a variety of molecules, which include neuropeptides, prostaglandins, cytokines, and excitatory amino acids. Nonetheless, in spite of the abundance of research aimed at elucidating the molecular mechanisms responsible for triggering, maintaining, and exacerbating pain, many questions still remain unanswered, and analgesic therapeutic options limited. Two accepted animal models that mimic neuropathic (NP) and inflammatory pain conditions are the L5-L6 spinal nerve ligation (SpNL), or Chung model, and the complete FreundÂ’s adjuvant-induced arthritis (CFA), respectively.

Our investigation of several neurotrophic factors in the SpNL model has led to some important findings: First, fibroblast growth factor-2 (FGF-2) mRNA was up-regulated in NP L5-L6 dorsal root ganglia (DRG) and FGF-2 immunoreactivity (IR) was increased in reactive dorsal horn (DH) astrocytes. Furthermore, using laser capture microdissection (LCM) coupled with RT-PCR, we also observed an increase in ipsilateral DH FGF-2 mRNA. FGF-2 is a pleiotropic cytokine with neurotrophic and gliogenic properties. While its role in cellular responses to various physical injuries to the brain and spinal cord has been extensively investigated, there is a paucity of data regarding FGF-2 in the setting of chronic pain. This is in spite of a number of studies showing an increase in both FGF-2 mRNA and/or protein in sensory ganglia in different animal models of neuropathy (Ji, 1995; Grothe, 1997; DeLeo, 1997; preliminary results). Our preliminary results add to this body of evidence by further suggesting that FGF-2 participates in at least one of the events induced by nerve injury, that is, astrocyte reactivity. This event, in turn, appears to be a vital component of the development of hyperalgesia/allodynia (DeLeo et al, 1997, 2001; Coyle, 1998). In inflammatory disorders, FGF-2 is increased in the inflamed joints of rats with adjuvant-induced arthritis (Qu, 1994) and of humans with rheumatoid arthritis (Bucala, 1991; Remmers, 1991; Nakashima , 1994; Qu , 1995; Manabe , 1999), where it contributes to inflammation, synovial angiogenesis, pannus formation, and joint destruction (Yamashita et al., 2002). Unfortunately, a more detailed investigation into the central contribution of FGF-2 in inflammatory pain is lacking at present.

Second, we have observed a significant increase in neuronal nerve growth factor (NGF) mRNA in ipsilateral L5-L6 DRG and DH by in situ hybridization (ISH) and LCM, respectively. Via immunohistochemistry, we have observed a decrease in NGF IR at 1-week post-ligation in the ipsilateral DH, with a significant recovery by 3-weeks to levels higher than in the contralateral side and in SHAM. These findings suggest that following nerve injury, which prevents the retrograde transport of NGF from the periphery (Raivich et al., 1991), novel signaling mechanisms are induced leading to newly synthesized NGF (Shen et al., 1999; Fukuoka et al., 2001; Oh et al., 2001). This newly produced NGF may be involved in the recovery of injured sensory fibers, as well as in the sprouting of non-injured nociceptive fibers (Romero et al., 2000; 2001) thereby contributing to the hyperalgesia observed in this model. Because FGF-2 has been shown to induce NGF synthesis in astrocytes, the early up-regulation of FGF-2 may be one of the mechanisms responsible for the increased NGF synthesis. Because NGF and astrocyte reactivity are associated with both SpNL and CFA models of pain (Bao et al., 2001; Coyle et al., 1998; Sweitzer et al., 2001; Pezet et al., 1999; 2001; appendix and preliminary results), comparing the contribution of FGF-2 to both NP pain (in the SpNL model) and inflammatory pain (CFA model) will improve our understanding of the mechanisms underlying nociception.

Other Expertise

Academic Experience:
National Scientific Advisory Committee for American Federation for Aging Research 1996-1997

Keywords

COS Keywords:

Biochemistry, Cell Biology, Genetics, Growth Factors, Membranes, Molecular Biology, Molecular Chemistry.

Additional Terms:

Cell Biology, Membrane Biochemistry, Molecular Biology.

Languages

(Reading, Writing, Speaking)

French: (Basic, Basic, Basic)
Spanish: (Functional, Basic, Functional)

Memberships

American College of Physicians
American College of Rheumatology

Previous Positions

1987-1990, University of Colorado Health Sciences Center, Research Fellow in Rheumatology
1986-1987, Columbia University College of Physicians and Surgeons, Clinical Fellow in Medicine

Funding Received

  • Searle Pharmaceuticals: , $168,500, Aug 1997 to Nov 1997.
  • National Institutes of Health (NIH): Chronic Pain, Supraspinal Serotonin and Neurotrophic Factors, $1,314,000, Apr 1, 2000 to Mar 31, 2004.
  • National Institutes of Health (NIH): Clinical Centers for the Osteoarthritis Initiative, $9,100,000, 7/15/02 to 5/14/09.
  • Cloning and Characterization of Murine FGF-1 Gene, National Institutes of Health (NIH), $413,018 1/1/92-12,96

Publications

  • Goettl VM, Hussain SR, Alzate O, Wirtz DJ, Stephens RL, Hackshaw KV., Differential change in mRNA expression of p75 and trk neurotrophin receptors in nucleus gracilis after spinal nerve ligation in the rat, Exp. Neurology, 187(533), 536, 2004
  • Madiai F, Jussain S-R, Goettl VM, Burry R, Stephens RL, Hackshaw KV, Upregulation of FGF-2 in reactive spinal cord astrocytes following unilateral lumbar spinal nerve ligation, Experimental Brain Research, 366-376, 2003
  • Goettl VM, Huang Y, Hackshaw KV, Stephens RL, Reduced basal release of serotonin from the ventrobasal thalamus of the rat in a model of neuropathic pain, Pain, 359 - 367, 2002
  • Whisler RL, Gray LS, Hackshaw KV, Rheumatology, a clinical overview, Clinics in Podiatric Medicine and Surgery, 149 - 161, 2002
  • Zhang Ying-Xue, Madiai F, Hackshaw KV, Cloning and characterization of a novel form of mouse fibroblast growth factor-1 (FGF-1) mRNA, FGF-1.G: Differential expression of FGF-1 and FGF-1.G mRNAs during embryonic development and in postnatal, Biochemica et Biophysica Acta, 45 - 58, 2001
  • Madiai F, Hackshaw KV, Chiu IM, Characterization of the entire transcription unit of the mouse fibroblast growth factor 1 \(FGF-1\) gene. Tissue-specific expression of the FGF-1.A mRNA., Journal of Biological Chemistry, 274(17), 11937-44, 23 Apr 1999 Abstract
  • Madiai F, Hackshaw KV, Lack of FGF-1 overexpression during autoimmune nephritis in the kidneys of MRL lpr/lpr mice., Res Commun Mol Pathol Pharmacol, 103(1), 37-44, Jan 1999 Abstract
  • Hackshaw KV, Lakshmanan RR, Everett RW, Fox CC, Downregulation of class II antigen expression by FGF-heparin complexes is due primarily to heparin effect., Res Commun Mol Pathol Pharmacol, 101(2), 99-114, August 1998 Abstract
  • Shah M H, Hackshaw K V, Caligiuri M A, A role for IL-15 in rheumatoid arthritis? [letter], Nature Medicine, 4(6), 643, June 1998 Abstract
  • Apseloff G, Hackshaw K V, Whitacre C, Weisbrode S E, Gerber N, Gallium nitrate suppresses lupus in MRL/lpr mice., Naunyn-schmiedebergs Archives of Pharmacology, 356(4), 517-25, October 1997 Abstract
  • Smart PA, Waylonis GW, Hackshaw KV, Immunologic profile of patients with fibromyalgia., American Journal of Physical Medicine and Rehabilitation, 76(3), 231-4, 1997 Abstract
  • Alam K Y, Frostholm A, Hackshaw K V, Evans J E, Rotter A, Chiu I M, Characterization of the 1B promoter of fibroblast growth factor 1 and its expression in the adult and developing mouse brain., Journal of Biological Chemistry, 271(47), 30263-71, 22 Nov 1996 Abstract
  • Hackshaw K V, Furlow Z M, Chiu I M, Cloning and characterization of a novel upstream untranslated exon of the mouse Fgf-1 gene., Gene, 180(1-2), 131-5, 21 Nov 1996 Abstract
  • Madiai F, Hackshaw K V, Chiu I M, Cloning and characterization of the mouse Fgf-1 gene., Gene, 179(2), 231-6, 14 Nov 1996 Abstract
  • Hackshaw K V, Trout A M, Acidic and basic fibroblast growth factors prolong the in-vitro survival of murine peritoneal macrophages., Research Communications In Molecular Pathology and Pharmacology, 92(3), 373-8, June 1996 Abstract
  • Hackshaw K V, Kunesh S L, Jackson N A, Culpepper C, Environmental influences on fatty acid composition of membranes from autoimmune MRL lpr/lpr mice., Prostaglandins Leukotrienes and Essential Fatty Acids, 54(4), 297-302, April 1996 Abstract
  • Liu B, Hackshaw K V, Whisler R L, Calcium signals and protein tyrosine kinases are required for the induction of c-jun in Jurkat cells stimulated by the T cell-receptor complex and oxidative signals., Journal of Interferon and Cytokine Research, 16(1), 77-90, January 1996 Abstract
  • Hackshaw K V, Shi Y, Brandwein S R, Jones K, Westcott J Y, A pilot study of zileuton, a novel selective 5-lipoxygenase inhibitor, in patients with systemic lupus erythematosus., Journal of Rheumatology, 22(3), 462-8, March 1995 Abstract
  • Whisler R L, Newhouse Y G, Grants I S, Hackshaw K V, Differential expression of the alpha- and beta-isoforms of protein kinase C in peripheral blood T and B cells from young and elderly adults., Mechanisms of Ageing and Development, 77(3), 197-211, 13 Jan 1995 Abstract
  • Whisler R L, Newhouse Y G, Beiqing L, Karanfilov B K, Goyette M A, Hackshaw K V, Regulation of protein kinase enzymatic activity in Jurkat T cells during oxidative stress uncoupled from protein tyrosine kinases: role of oxidative changes in protein kinase activation requirements a, Lymphokine and Cytokine Research, 13(6), 399-410, December 1994 Abstract
  • Hackshaw K V, Jackson N A, Shi Y, Composition of peritoneal macrophage membranes in autoimmune MRL lpr/lpr mice., Life Sciences, 55(10), 767-73, 1994 Abstract
  • Hackshaw K V, Shi Y, Fibroblast growth factors mobilize peritoneal macrophage intracellular calcium., Life Sciences, 54(10), 661-70, 1994 Abstract
  • Hackshaw K V, Voelkel N F, Thomas R B, Westcott J Y, Urine leukotriene E4 levels are elevated in patients with active systemic lupus erythematosus., Journal of Rheumatology, 19(2), 252-8, February 1992 Abstract
  • Liu B, Hackshaw KV, Whisler RL. Calcium Signals and Protein Tyrosine Kinases are Required for the Induction of C-Jun in Jurkat Cells Stimulated by the T Cell Receptor Complex and Oxidative Signals. Lymphokine and Cytokine Research, 16: 77-90, 1996
  • Liu B, Hackshaw KV, Whisler RL. Calcium Signals and Protein Tyrosine Kinases are Required for the Induction of C-Jun in Jurkat Cells Stimulated by the T Cell Receptor Complex and Oxidative Signals. Lymphokine and Cytokine Research, 16: 77-90, 1996
  • Madiai F, Hackshaw KV, Chiu I-M. Cloning and Characterization of Murine FGF-1 Gene. Gene 179: 231-236, 1996
  • Hackshaw KV, Furlow ZM, Chiu I-M. Characterization of an Upstream Untranslated Exon from Mouse FGF-1 Gene. Gene 180: 131-135, 1996
  • Hackshaw KV, Trout AM. Acidic and Basic Fibroblast Growth Factors Prolong the Invitro Survival of Murine Peritoneal Macrophages. Res Commun Mol Path & Pharm, 92: 373-378, 1996 pub6:14. Alam K, Frostholm A, Hackshaw KV, Evans JA, Rotter A, Chiu I-M. Characterization of the 1B Promoter of Fibroblast Growth Factor Promoter 1 (FGF-1B) and its Expression in the Adult and Developing Mouse Brain. Jrnl Biol Chem 271: 30263-30271, 1996

Profile Details

Last Updated: 7/2/2004

COS Expertise ID #410807
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