Long Range Goals
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R. LEE MOSLEY, PhD
Durham Research Center II, Room 3062
985930 Nebraska Medical Center
Omaha, NE 68198-5930
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Keywords: Immunoregulation, Neurodegeneration, Neuroprotection, Immunology, Vaccine, T Cell, Inflammation, Parkinson's disease, MPTP, Amyotrophic lateral sclerosis (ALS)
Many neurodegenerative diseases exhibit inflammatory components, which have been shown to play integral roles in neurodegenerative processes.
In models of Alzheimer's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), and experimental allergic encephalitis (EAE, a model for multiple sclerosis), chronic inflammation is a dominant feature, whereas acute inflammatory responses appear essential in murine models for HIV-1-induced encephalitis and Parkinson's disease. In the latter model, dopaminergic-specific neurodegeneration is induced by the dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Proinflammatory cytokines, common to these models as well as responses induced by and type 1 T helper cells (Th1), IL-17A-producing Th cells (Th17), and type 1 cytotoxic T cells (Tc1) responses, exacerbate neurodegenerative processes, whereas suppression of proinflammatory cytokine expression mediated by anti-inflammatory pharmaceuticals or cytokines affords neuroprotection and/or neuroregeneration. Unfortunately, the benefits these modalities are either transient or subjects become refractory to therapy.
Our objective is to develop vaccine strategies that induce and sustain type 2 or type 3 anti-inflammatory T cell (Th2 and Th3) or regulatory T cell (Treg) responses, which interdict proinflammatory processes with subsequent amelioration of neurodegenerative processes and promotion of neuroprotection and/or neuroregeneration. Strategies for neuroprotective vaccines are proposed that preferentially mediate anti-inflammatory responses.
In our animal models, monitoring of disease progression or regression is afforded by noninvasive analyses using single photon emission computed tomography (SPECT), magnetic resonance (MR), and MR spectroscopic (MRS) imaging. Combined with conventional immunological assessment, sera and immune cell or neuronal tissue products from vaccinated subjects are evaluated for normal or unique cytokine profiles by proteomic analysis that collectively utilized new technologies of protein chip adsorption, surface enhanced laser desorption/ionization (SELDI) mass spectroscopy, and ion-trap mass spectroscopy-based protein sequencing. Together, novel vaccine strategies with higher resolution assessment of vaccine efficacies will facilitate greater translational potentials for future therapeutic modalities.
- Vaccine strategies in MPTP mouse model of Parkinson's disease and mutated human SOD transgenic mouse model of ALS. To date, no curative or interventional modalities exist for Parkinson's disease or ALS. We demonstrated that adoptive transfer of T cells from donors vaccinated with Copaxone, an indicated drug for multiple sclerosis, ameliorates dopaminergic neurodegeneration in the MPTP mouse model of Parkinson's disease. More recently, we have shown that natural and adaptive regulatory T cells (Tregs) effectively attenuate neuroinflammation and protects against neurodegeneration. Thus, the major goals of this research project are to define the neuroprotective mechanisms by which natural and induced regulatory T cells function and delineate efficacious therapeutic vaccine strategies that increase Treg function to provide augmented protection in neurodegenerative disorders.
- Mechanisms of T cell-mediated regulation of neurodegeneration in Parkinson's disease and ALS. Microglial inflammation plays a major contributing role in several neurodegenerative disorders. Oxidatively-modified proteins such as α-synuclein not only induce microglial inflammation but also are recognized by the adaptive immune system. We have shown in the MPTP model of Parkinson's disease that T cells from nitrated α-synuclein immune donors exacerbate neuroinflammation and neurodegeneration, thus provide an added mechanism by which Parkinson's disease progresses. The goals for this research program address cellular and molecular mechanisms by which adaptive T cell immunity exacerbate microglial inflammation and drive neurodegeneration in Parkinson's disease. These mechanisms will serve as candidate targets for therapeutic strategies to interdict the inflammatory and degenerative cycles in neurodegenerative disorders.
- Immune effector cell trafficking by non-invasive SPECT imaging. Until recently, immune effector cell trafficking into the brain was thought to be minimal or have minimal effect; however, recent evidence indicates that both monocyte- and lymphocyte-derived effector cells can profoundly influence disease progression and neuropathy in mouse models of HIV-1 encephalitis and MPTP-induced Parkinson's disease. With the advent of SPECT and MR imaging technologies dedicated to small animal research, non-invasive and longitudinal evaluation of immune effector cell migration into the brain is now possible. Our goals for this research project is to delineate kinetic migration patterns for subsets of immune effector populations and determine the mechanisms by which HIV-1 encephalitis and MPTP-induced inflammatory responses regulate effector cell trafficking into the brain and surrounding lymphoid tissues.
- Effects of aging on the T cell repertoire and immune system. With age, peripheral T lymphocyte function is effectively downregulated; however, the mechanisms responsible for age-associated diminution of T cell function are still not fully understood. In Parkinson's disease, for which age is the most prevalent risk factor, anomalies in peripheral T cell subsets are consistently observed. Recent evidence of idiosyncratically skewed representations of T cell receptor variable region of the beta chain families among both CD4+ and CD8+ T cells of elderly humans and aged mice suggests that clonal sequestration of T cells provide yet another mechanism for age-related alterations in T cell function and that declination of the neuroregulatory T cell repertoire is permissive for age- associated neuroinflammation and neurodegeneration associated with Parkinson's disease. The major goals of these studies address mechanistic and functional implications of age-related deviations in the peripheral T cell repertoire of aged mice. Findings of age-related repertoire contraction by accumulation of T cell subsets with different mechanisms for survival will have important implications for vaccination strategies and may further impact explanations of autoimmunity and age-associated susceptibility to infectious, neoplastic and neurodegenerative diseases.
The long-range goals of this laboratory are to delineate the etiological or exacerbative mechanisms of neurodegenerative disorders and develop therapeutic modalities that target those mechanisms to interdict the degenerative/inflammatory cycle and provide support for adjunct regenerative therapies.
- Mosley, RL and Gendelman, H.E. 2010. Control of neuroinflammation as a therapeutic strategy for amyotrophic lateral sclerosis and other neurodegenerative disorders. Exp Neurol. 2010 Mar;222(1):1-5
- Kosloski LM, Ha DM, Hutter JA, Stone DK, Pichler MR, Reynolds AD, Gendelman HE, Mosley RL. Adaptive immune regulation of glial homeostasis as an immunization strategy for neurodegenerative diseases. J Neurochem. 2010 Sep 1;114(5):1261-76
- Liu Y, Uberti M, Mosley RL, Gendelman HE, Boska M. 2009. An image warping technique for rodent brain MRI-histology registration based on thin-plate splines with landmark optimization. Proc. SPIE Med. Imaging, (in press)
- Uberti M, Liu Y, Dou H, Mosley RL, Gendelman HE, Boska M. 2009. Registration of in vivo MR to histology of rodent brains using blockface imaging. Proc. SPIE Med. Imaging (in press)
- Stone DK, Reynolds AD, Mosley RL, Gendelman HE. 2009. Forum review: Innate and Adaptive Immunity for the Pathobiology of Parkinson’s Disease. Antioxid Redox Signal 11(9):2151-66
- Gendelman HE, Ding S, Gong N, Liu J, Ramirez SH, Persidsky Y, Mosley RL, Wang T, Volsky DJ, Xiong H. 2009. Monocyte chemotactic protein-1 regulates voltage-gated K+ channels and macrophage transmigration. J Neuroimmune Pharmacol 4:47-59
- Beduneau A, Ma Z, Grotepas CB, Kabanov A, Rabinow BE, Gong N, Mosley RL, Dou H, Boska, MD, Gendelman HE. 2009. Facilitated monocyte-macrophage uptake and tissue distribution of superparamagnetic iron-oxide nanoparticles.PLoS One 4:e4343
- Liu L, Gong N, Huang X, Reynolds AD, Mosley RL, Gendelman HE. 2009. Neuromodulatory activities of CD4+CD25+ regulatory T cells in a murine model of HIV-1 associated neurodegeneration. J Immunol 182:3855-65
- Reynolds AD, Stone DK, Mosley RL, Gendelman HE. 2009. Nitrated alpha synuclein induced alterations in microglial immunity is regulated by CD4+ T cell subsets. J Immunol 182:4137-49
- Banerjee R, Mosley RL, Reynolds AD, Dhar A, Jackson-Lewis V, Gordon PH, Przedborski S, Gendelman HE. 2008. Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice. PLoS ONE. 3:e2740
- Schlautman JD, Rozek W, Stetler R, Mosley RL, Gendelman HE, Ciborowski P. 2008. Multidimensional protein fractionation using ProteomeLab PF 2Dtrade mark for profiling amyotrophic lateral sclerosis immunity: A preliminary report. Proteome Sci. 6:26-37
- Wang T, Gong N, Liu J, Kadiu I, Kraft-Terry SD, Mosley RL, Volsky DJ, Ciborowski P, Gendelman HE. 2008. Proteomic modeling for HIV-1 infected microglia-astroctye crosstalk. PLoS ONE. 3:e2507
- Benner EJ, Banerjee R, Nemachek C, Ciborowski P, Przedborski S, Mosley RL, Gendelman HE. 2008. Nitrated α–synuclein induced adaptive immunity accelerates dopaminergic neuronal degeneration in a murine model of Parkinson’s disease. PLoS ONE 3:e1376
Additional publications on PubMed.gov
Dr. Mosley's biographical information
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