Browsing by Author "Vitek, Michael P"

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    ApoE mimetic ameliorates motor deficit and tissue damage in rat spinal cord injury.
    (Journal of neuroscience research, 2014-07) Wang, Ruihua; Hong, Jun; Lu, Miaomiao; Neil, Jessica E; Vitek, Michael P; Liu, Xiaozhi; Warner, David S; Li, Fengqiao; Sheng, Huaxin
    Apolipoprotein E (apoE), a plasma protein responsible for transporting lipid and cholesterol, modulates responses of the central nervous system to injury. Small peptides derived from the receptor-binding region of apoE can simulate some important bioactivities of apoE holoprotein and offer neuroprotection against brain injury. We tested whether COG1410, an apoE-mimetic peptide, provides protection in a rat model of spinal cord injury (SCI). Traumatic injury was created at T8 by a cortical impact device. Injured rats were randomized to four treatment groups: vehicle, 0.15, 0.3, or 0.6 mg/kg COG1410; sham surgery rats received vehicle. Basso, Beattie, Bresnahan neurological score was evaluated prior to injury and at 1, 3, 7, and 14 days after injury. Histological changes were evaluated at 14 days. All injured rats lost body weight during the first week following injury. Body weight recovery was significantly improved in rats treated with COG1410. Mechanical impact resulted in severe motor deficit, and most animals had a BBB score of 0-1 at 24 hours postinjury. COG1410-treated rats showed significantly improved functional recovery and ameliorated motor deficit at 14 days postinjury. Histological analysis showed that COG1410 groups had a significantly reduced lesion size at the site of injury, a larger preserved luxol fast blue-stained area, and more visible neurons in the surrounding area of injury. Microglial activation was also significantly suppressed. These findings indicate that this apoE mimetic effectively improved neurological and histological outcome following SCI in rats, and the effect was associated with inhibition of microglial activation.
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    Apolipoprotein E Mimetic Promotes Functional and Histological Recovery in Lysolecithin-Induced Spinal Cord Demyelination in Mice.
    (J Neurol Neurophysiol, 2013-04) Gu, Zhen; Li, Fengqiao; Zhang, Yi Ping; Shields, Lisa BE; Hu, Xiaoling; Zheng, Yiyan; Yu, Panpan; Zhang, Yongjie; Cai, Jun; Vitek, Michael P; Shields, Christopher B
    OBJECTIVE: Considering demyelination is the pathological hallmark of multiple sclerosis (MS), reducing demyelination and/or promoting remyelination is a practical therapeutic strategy to improve functional recovery for MS. An apolipoprotein E (apoE)-mimetic peptide COG112 has previously demonstrated therapeutic efficacy on functional and histological recovery in a mouse experimental autoimmune encephalomyelitis (EAE) model of human MS. In the current study, we further investigated whether COG112 promotes remyelination and improves functional recovery in lysolecithin induced focal demyelination in the white matter of spinal cord in mice. METHODS: A focal demyelination model was created by stereotaxically injecting lysolecithin into the bilateral ventrolateral funiculus (VLF) of T8 and T9 mouse spinal cords. Immediately after lysolecithin injection mice were treated with COG112, prefix peptide control or vehicle control for 21 days. The locomotor function of the mice was measured by the beam walking test and Basso Mouse Scale (BMS) assessment. The nerve transmission of the VLF of mice was assessed in vivo by transcranial magnetic motor evoked potentials (tcMMEPs). The histological changes were also examined by by eriochrome cyanine staining, immunohistochemistry staining and electron microscopy (EM) method. RESULTS: The area of demyelination in the spinal cord was significantly reduced in the COG112 group. EM examination showed that treatment with COG112 increased the thickness of myelin sheaths and the numbers of surviving axons in the lesion epicenter. Locomotor function was improved in COG112 treated animals when measured by the beam walking test and BMS assessment compared to controls. TcMMEPs also demonstrated the COG112-mediated enhancement of amplitude of evoked responses. CONCLUSION: The apoE-mimetic COG112 demonstrates a favorable combination of activities in suppressing inflammatory response, mitigating demyelination and in promoting remyelination and associated functional recovery in animal model of CNS demyelination. These data support that apoE-mimetic strategy may represent a promising therapy for MS and other demyelination disorders.
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    Caspase-1 and the inflammasome promote polycystic kidney disease progression.
    (Frontiers in molecular biosciences, 2022-01) Swenson-Fields, Katherine I; Ward, Christopher J; Lopez, Micaila E; Fross, Shaneann; Heimes Dillon, Anna L; Meisenheimer, James D; Rabbani, Adib J; Wedlock, Emily; Basu, Malay K; Jansson, Kyle P; Rowe, Peter S; Stubbs, Jason R; Wallace, Darren P; Vitek, Michael P; Fields, Timothy A
    We and others have previously shown that the presence of renal innate immune cells can promote polycystic kidney disease (PKD) progression. In this study, we examined the influence of the inflammasome, a key part of the innate immune system, on PKD. The inflammasome is a system of molecular sensors, receptors, and scaffolds that responds to stimuli like cellular damage or microbes by activating Caspase-1, and generating critical mediators of the inflammatory milieu, including IL-1β and IL-18. We provide evidence that the inflammasome is primed in PKD, as multiple inflammasome sensors were upregulated in cystic kidneys from human ADPKD patients, as well as in kidneys from both orthologous (PKD1 RC/RC or RC/RC) and non-orthologous (jck) mouse models of PKD. Further, we demonstrate that the inflammasome is activated in female RC/RC mice kidneys, and this activation occurs in renal leukocytes, primarily in CD11c+ cells. Knock-out of Casp1, the gene encoding Caspase-1, in the RC/RC mice significantly restrained cystic disease progression in female mice, implying sex-specific differences in the renal immune environment. RNAseq analysis implicated the promotion of MYC/YAP pathways as a mechanism underlying the pro-cystic effects of the Caspase-1/inflammasome in females. Finally, treatment of RC/RC mice with hydroxychloroquine, a widely used immunomodulatory drug that has been shown to inhibit the inflammasome, protected renal function specifically in females and restrained cyst enlargement in both male and female RC/RC mice. Collectively, these results provide evidence for the first time that the activated Caspase-1/inflammasome promotes cyst expansion and disease progression in PKD, particularly in females. Moreover, the data suggest that this innate immune pathway may be a relevant target for therapy in PKD.
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    Inhibition of Pten deficient Castration Resistant Prostate Cancer by Targeting of the SET - PP2A Signaling axis.
    (Sci Rep, 2015-11-13) Hu, Xiaoyong; Garcia, Consuelo; Fazli, Ladan; Gleave, Martin; Vitek, Michael P; Jansen, Marilyn; Christensen, Dale; Mulholland, David J
    The PP2A signaling axis regulates multiple oncogenic drivers of castration resistant prostate cancer (CRPC). We show that targeting the endogenous PP2A regulator, SET (I2PP2A), is a viable strategy to inhibit prostate cancers that are resistant to androgen deprivation therapy. Our data is corroborated by analysis of prostate cancer patient cohorts showing significant elevation of SET transcripts. Tissue microarray analysis reveals that elevated SET expression correlates with clinical cancer grading, duration of neoadjuvant hormone therapy (NHT) and time to biochemical recurrence. Using prostate regeneration assays, we show that in vivo SET overexpression is sufficient to induce hyperplasia and prostatic intraepithelial neoplasia. Knockdown of SET induced significant reductions in tumorgenesis both in murine and human xenograft models. To further validate SET as a therapeutic target, we conducted in vitro and in vivo treatments using OP449 - a recently characterized PP2A-activating drug (PAD). OP449 elicits robust anti-cancer effects inhibiting growth in a panel of enzalutamide resistant prostate cancer cell lines. Using the Pten conditional deletion mouse model of prostate cancer, OP449 potently inhibited PI3K-Akt signaling and impeded CRPC progression. Collectively, our data supports a critical role for the SET-PP2A signaling axis in CRPC progression and hormone resistant disease.
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    Surpassing the emerging immune-checkpoint inhibitor market
    (CANCER IMMUNOLOGY RESEARCH, 2016-01) Vitek, Michael P
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    Translational animal models for Alzheimer's disease: An Alzheimer's Association Business Consortium Think Tank.
    (Alzheimer's & dementia (New York, N. Y.), 2020-01) Vitek, Michael P; Araujo, Joseph A; Fossel, Michael; Greenberg, Barry D; Howell, Gareth R; Rizzo, Stacey J Sukoff; Seyfried, Nicholas T; Tenner, Andrea J; Territo, Paul R; Windisch, Manfred; Bain, Lisa J; Ross, April; Carrillo, Maria C; Lamb, Bruce T; Edelmayer, Rebecca M
    Over 5 million Americans and 50 million individuals worldwide are living with Alzheimer's disease (AD). The progressive dementia associated with AD currently has no cure. Although clinical trials in patients are ultimately required to find safe and effective drugs, animal models of AD permit the integration of brain pathologies with learning and memory deficits that are the first step in developing these new drugs. The purpose of the Alzheimer's Association Business Consortium Think Tank meeting was to address the unmet need to improve the discovery and successful development of Alzheimer's therapies. We hypothesize that positive responses to new therapies observed in validated models of AD will provide predictive evidence for positive responses to these same therapies in AD patients. To achieve this goal, we convened a meeting of experts to explore the current state of AD animal models, identify knowledge gaps, and recommend actions for development of next-generation models with better predictability. Among our findings, we all recognize that models reflecting only single aspects of AD pathogenesis do not mimic AD. Models or combinations of new models are needed that incorporate genetics with environmental interactions, timing of disease development, heterogeneous mechanisms and pathways, comorbidities, and other pathologies that lead to AD and related dementias. Selection of the best models requires us to address the following: (1) which animal species, strains, and genetic backgrounds are most appropriate; (2) which models permit efficient use throughout the drug development pipeline; (3) the translatability of behavioral-cognitive assays from animals to patients; and (4) how to match potential AD therapeutics with particular models. Best practice guidelines to improve reproducibility also need to be developed for consistent use of these models in different research settings. To enhance translational predictability, we discuss a multi-model evaluation strategy to de-risk the successful transition of pre-clinical drug assets to the clinic.
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    Traumatic brain injury exacerbates neurodegenerative pathology: improvement with an apolipoprotein E-based therapeutic.
    (J Neurotrauma, 2010-11) Laskowitz, Daniel T; Song, Pingping; Wang, Haichen; Mace, Brian; Sullivan, Patrick M; Vitek, Michael P; Dawson, Hana N
    Cognitive impairment is common following traumatic brain injury (TBI), and neuroinflammatory mechanisms may predispose to the development of neurodegenerative disease. Apolipoprotein E (apoE) polymorphisms modify neuroinflammatory responses, and influence both outcome from acute brain injury and the risk of developing neurodegenerative disease. We demonstrate that TBI accelerates neurodegenerative pathology in double-transgenic animals expressing the common human apoE alleles and mutated amyloid precursor protein, and that pathology is exacerbated in the presence of the apoE4 allele. The administration of an apoE-mimetic peptide markedly reduced the development of neurodegenerative pathology in mice homozygous for apoE3 as well as apoE3/E4 heterozygotes. These results demonstrate that TBI accelerates the cardinal neuropathological features of neurodegenerative disease, and establishes the potential for apoE mimetic therapies in reducing pathology associated with neurodegeneration.