1997 — 2001 |
Persidsky, Yuri |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Biological Basis For Hiv1 Neurovirulence @ University of Nebraska Medical Center
DESCRIPTION (adapted from the Abstract): The neuropathogenesis of HIV encephalitis and HIV dementia is associated with sustained viral replication in brain macrophages and microglia. Viral penetration of the BBB and productive infection of brain macrophages appears necessary but not sufficient for the development of neurological abnormalities. Therefore, the hypothesis of interest is that specific viral neurotropic strains may produce qualitative changes in brain function resulting in macrophage effector molecule neurotoxin release. In addition, different strains of HIV-1 could produce qualitatively distinct central nervous system (CNS) abnormalities that affect monocyte transendothelial migration and production of toxins. To assess the role of specific HIV-1 strains in viral neuropathogenesis, the Investigator plans to study virologic, cellular immune, and functional outcomes of virus-macrophage interactions. Utilizing a blood/brain barrier system in the SCID mouse model of HIV encephalitis, he and his associates will propagate large numbers of microglia and blood monocytes to perform interactive experiments that could validate the hypothesis that different HIV-1 strains could produce distinct CNS pathological lesions. These studies will provide a rationale to address scientifically whether specific HIV-1 strains induce changes, qualitative and quantitative, in macrophage function that affect CNS neuroimmune interactions leading to progressive neurological disease in AIDS.
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0.961 |
2002 — 2006 |
Persidsky, Yuri |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Bbb Tight Junctions During Hiv-1 Dementia @ University of Nebraska Medical Center
DESCRIPTION (provided by applicant): It is generally agreed that the blood-brain barrier (BBB) is impaired in HIV-1 associated dementia (HAD). However, the mechanism for BBB dysfunction is not well understood. Post-mortem examination of brain tissue from subjects with HIV-1 encephalitis (HIVE) revealed that brain microvascular endothelial cell (BMVEC) tight junction (TJ) integrity is diminished and can be correlated with macrophage egress and HAD. How immune competent HIV-1 -infected macrophages influence BMVEC TJ expression and function resulting in BBB compromise is the focus of the proposal. To address this, we asked the following questions: 1) Do immune- activated and/or virus-infected monocytes affect BMVEC TJ assembly? 2) Can modulation of key signaling pathways (such as Rho) for regulation of cytoskeletal organization in BMVEC alter TJ function? 3) Can inhibition of Rho prevent monocyte migration into brain during HIVE? We will employ (a) primary cell models, (b) a functional BBB model consisting of BMVEC and astrocytes seeded on opposing sides of a porous membrane, and (c) a novel xenograft system for HIVE in which peripheral human peripheral blood lymphocytes and monocytes have been shown to migrate into brain parenchyma. These will provide clues about how TJ integrity may be manipulated pharmacologically. Such studies should have broad relevance in the pathogenesis of a wide range of neurodegenerative disorders.
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0.961 |
2002 — 2004 |
Persidsky, Yuri |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Effect of Alcohol On Hiv-1 Immune Responses &Bbb Damage @ University of Nebraska Medical Center
DESCRIPTION (provided by applicant): Neuro-cognitive deficits observed in chronic alcoholics often mirror those observed in individuals with HIV-1 associated dementia (HAD). Given the patterns of similarity including neuropathological changes (neuronal dropout and decreased dendrite density) in HAD patients and alcohol abusers, it has been suggested that alcohol may serve as an accomplice in development on HAD and exacerbate the symptoms. Indeed, it has been shown that CNS suffers the additive effects of alcohol abuse and HIV infection. The mechanisms of such synergy remain elusive. It is generally agreed that the blood-brain barrier (BBB) is impaired in HAD and involves loss of tight junction (TJ) integrity. In addition, white matter abnormalities observed in chronic alcoholics are related to changes in BBB function. In this proposal, we attempt to evaluate the mechanism of alcohol-related modulation of HIV-1 encephalitis (HIVE). We hypothesize that alcohol abuse leads to direct alterations in monocyte migration during HIVE and that alcohol alters CNS immune responses through exacerbated BBB dysfunction. We will utilize our well-established model systems to study BBB changes in context of alcohol and HIV-1. We also propose exploratory studies to address specific cellular mechanisms underlying these phenomena. For this purpose, we will examine the myosin light chain kinase (MLCK) pathway of TJ disassembly in BBB and alterations in proteasomal function in endothelial cells and macrophages. To test these hypotheses, we will address three specific questions: 1) What are the effects of alcohol on monocyte migration across the BBB in HIVE? 2) Does BBB dysfunction due to TJ disassembly play a role in the impaired immune responses in HIVE? and 3) What are the possible mechanisms involved in alcohol-induced alterations in endothelial cell and macrophage function? We will employ a functional BBB model consisting of primary endothelial cells and astrocytes to study TJ disassembly, a xenograft animal model system for HIVE to evaluate in vivo immune responses and BBB dysfunction, and primary human cell models to decipher intracellular mechanisms. The ability to use an in vitro BBB and an in vivo animal model will help in defining mechanisms of disease progression in the setting of alcohol abuse.
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0.961 |
2003 — 2006 |
Persidsky, Yuri |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Microglial Deactivation and Hiv Dementia @ University of Nebraska Medical Center
Mononuclear phagocytes (MP, microglia and perivascular macrophages) serve as targets for productive human immunodeficiency virus type-1 (HIV-1) infection within the central nervous system. Neuroimmune events leading to HIV-1-associated dementia (HAD) are associated with MP secretory products (cellular and viral toxins) produced during HIV-1 encephalitis (HIVE). Laboratory, animal model and postmortem brain tissue studies of HIVE uniformly demonstrate that microglial activation, not the absolute level of virus, is the best correlate for cognitive impairment during HAD. Based on these observations this project will investigate the role of microglial deactivation in pathogenesis of HAD in HIVE SCID model. The established infrastructure of our Center for Neurovirology and Neurodenegerative Disorders (CNND) will be utilized to explore the means to abrogate microglial activation in our experimental animal model of HIVE that reflects the biologic, immune and pathophysiologic effects of HIV-1 replication in brain MP. Specifically, we hypothesize that inhibition of kynurenine pathway in activated microglia leads to a reduction in the neurotoxic potential of these cells and results in cognitive improvement. To test this hypothesis, the following questions will be addressed: 1) What are the contributions of the kynurenine pathway in microglial activation and the consequential neurotoxic activities of immune activated and/or virus activated MP in HAD? 2) Is inhibition of kynurenine pathway in activated microglia a crucial link to improved clinical symptoms? & 3) Does inhibition of kynurenine pathway in activated microglia change neuronal function in the context of HAD neuropathogenesis? We will evaluate effects of MP deactivation via kynurenine pathway on neuro-inflammatory responses, neuronal dysfunction, and cognitive impairment in the HIVE SCID mouse model and correlate these observations with in vitro and ex vivo studies on MP. These works will allow us to investigate novel aspects of neuroimmunology and establish a link between immune and cognitive functions. The potential findings have broad relevance in pathogenesis of a wide range of neurodegenerative disorders beyond HAD. The integration between this project and the others is in serving to best understand the role of microglial immunity in the neuropathogenesis of HIV-1 disease.
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0.961 |
2005 — 2009 |
Persidsky, Yuri |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Ppar-Gamma-Mediated Neuroprotection Against Hiv-1 and Alcohol Cns Injury @ Temple Univ of the Commonwealth
DESCRIPTION (provided by applicant): Neuro-cognitive deficits observed in chronic alcoholics often mirror those in individuals with HIV-1-associated dementia (HAD). It has been suggested that alcohol abuse may serve as a co-factor in the development of HAD and exacerbate the symptoms of HIV-1 encephalitis (HIVE). We have previously shown that ethanol affects macrophage function (antigen presentation) and the blood brain barrier (BBS) by enhancing monocyte infiltration via disruption of tight junctions. We further demonstrated that the combined effects of alcohol abuse and HIV-1 infection affect adaptive immune responses and augment neuroinflammation in a small animal model of HIVE. These evidences support the idea that alcohol abuse is an exacerbating factor in HIV-1 central nervous system (CMS) infection through BBB damage and augmented neuroinflammation leading to neuronal injury and diminished anti-viral adaptive immunity. We propose that activation of peroxisome proliferator-activated receptor gamma (PPARgamma, an anti-inflammatory regulatory pathway) diminishes inflammatory cell activation in the CMS, alters their neurotoxic potential and renders protective effects. PPARgamma stimulation in endothelial cells can prevent monocyte transmigration to the brain in the setting of alcohol abuse and HIV-1 infection. In this competing continuation, we will investigate the therapeutic potential of PPARgamma activation and the mechanisms involved in PPARgamma-mediated amelioration of the combined deleterious effects of alcohol abuse by addressing the following questions: 1) Can PPARgamma stimulation alter the neuroprotective/neurotoxic potential of HIV-1-infected, immune activated macrophages [through cytokine and glutamate production, activation of inducible nitric oxide synthase and generation of reactive oxygen species, (ROS)]? 2) Can PPARgamma stimulation attenuate neuroinflammation by decreasing monocyte migration across the BBB (via up-regulation of ROS scavenging enzyme, superoxide dismutase)? And 3) Can PPARgamma agonists diminish neuroinflammation, improve BBB dysfunction and restore impaired immune responses associated with alcohol abuse in an animal model for HIVE? These studies will use cellular models, BBB constructs and an animal model for HIVE to mechanistically address putative protective effects of PPARgamma stimulation on BBB and neurons damaged by alcohol and interactions with HIV-1-infected macrophages. Since the last submission, we obtained additional data (namely significant anti-inflammatory and anti-viral effects of PPARgamma agonists) in support of the hypothesis being tested. The availability of PPARgamma agonists approved for clinical use will permit rapid translation of experimental findings into therapeutic applications.
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1 |
2007 — 2011 |
Persidsky, Yuri |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Bbb Protection in Hiv-1 Dementia: Anti-Inflammatory Effects of Gsk-3beta Suppres @ Temple Univ of the Commonwealth
DESCRIPTION (provided by applicant): Blood-brain barrier (BBB) compromise is one of the underlying causes of HIV-1 associated dementia (HAD). Diminished expression of brain microvascular tight junctions (TJ) is observed in brain tissues of HAD patients indicating BBB injury. During the previous period of funding, we established that activation of small dimeric G-proteins (Rho GTPases, such as RhoA) played a central role in alterations of BMVEC TJ. RhoA inhibition prevented migration of HIV-1 infected monocytes, TJ changes and diminished permeability of the BBB. We identified soluble factors that disrupted the barrier and increased monocyte migration across the BBB. We believe that widespread BBB injury seen in areas devoid of leukocyte infiltration could be due to effects of such small molecules produced by activated HIV-1 infected macrophages on the brain side of the barrier. Thus, pro-inflammatory molecules secreted by HIV-1 infected/activated macrophages and interactions between brain endothelial cells and monocytes are two major factors contributing to BBB abnormalities. In addition, our preliminary data indicated that inhibition of glycogen synthase kinase (GSK)-3? prevented activation of Rho GTPases in BMVEC and monocytes, decreased monocyte migration through the BBB and reduced production of inflammatory molecules by activated macrophages, preserving BBB. Recently, GSK-3? inhibitors were recognized as a therapeutic option for HAD treatment due to their direct neuroprotective properties. However, powerful immunomodulatory effects of GSK-3? inhibition have received much less attention in neurodegeneration. GSK-3? suppression as an anti-inflammatory treatment strategy for BBB injury in HAD is the focus of the current proposal. In this competing continuation, we will investigate the therapeutic potential of GSK-3? inhibition and the mechanisms through which it can curtail BBB compromise by addressing the following questions: 1) How GSK-3? inhibition diminishes monocyte migration across the BBB? 2) Can GSK-3? suppression decrease secretion of pro-inflammatory factors in activated HIV-1 infected macrophages attenuating their effects on the BBB? and 3) Can GSK-3? inhibitors prevent BBB dysfunction in an animal model for HIVE via their anti-inflammatory effects? The proposed works will uncover novel mechanisms underlying the immunomodulatory effects of GSK-3? suppression and are highly significant for amelioration of BBB dysfunction in HIV-1 dementia.
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1 |
2007 — 2012 |
Haorah, James (co-PI) [⬀] Persidsky, Yuri |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Alcohol Abuse and Hiv-1: Mechanisms of Combined Cns Injury and Interventions @ Temple Univ of the Commonwealth
DESCRIPTION (provided by applicant): Alcohol is the most commonly used and abused drug in the United States. Deleterious alcohol-related health effects, attributed to internal organ toxicity, include irreversible brain tissue injury. Brain tissue of chronic alcoholics features neurodegeneration paralleling neuro-cognitive deficits. The causes of HIV-1-associated neurotoxicity, clinically manifesting as HIV-1 associated dementia (HAD), include excitotoxic effects of glutamate, secretory products of chronically activated glial cells, and oxidative stress, similar culprits to ones mediating alcohol-induced neuronal injury. Alcohol abuse and HIV-1 infection of central nervous system (CNS) could result in combined toxic effects leading to neuronal demise and cognitive dysfunction. The current grant application is focused on putative mechanisms of enhanced neurotoxicity in the setting of alcohol abuse and HIV-1 CNS infection. Specifically, we will study unique aspects of astrocyte dysfunction caused by HIV-1 CNS infection and alcohol abuse. We hypothesize that astrocyte dysfunction caused by alcohol metabolites and oxidative stress results in (1) increased glutamate levels via down regulation of excitatory amino acid transporter (EAAT-2, the primary astrocyte glutamate scavenger) causing neuronal injury; (2) production of pro-inflammatory factors (via activation of Src kinases and phospholipase A2); and (3) enhanced activity of metalloproteases (MMPs) resulting in loss of blood brain barrier (BBB) integrity. We mechanistically address the role of oxidative stress in astrocytes leading to production of pro-inflammatory molecules and impairment of glutamate uptake by astrocytes. Using a combination of in vitro systems, an HIVE animal model chronically exposed to alcohol, and in vivo magnetic resonance spectroscopy, we will investigate the astrocyte dysfunction as a focal point of combined effects of HIV-1 and alcohol abuse in the CNS. We will address the following questions: (1) What are the underlying mechanisms causing astrocyte pro-inflammatory phenotype in the setting of alcohol abuse and HIV-1 CNS infection that cause activation of MMPs and BBB dysfunction? (Aim 1); (2) What is the role/contribution of enhanced production of reactive oxygen species, Rho GTPases, and NF-?B signaling in diminished expression and function of EAAT-2 in astrocytes? (Aim 2); (3) How effective are the therapeutics that target oxidative stress and EAAT-2 dysregulation in ameliorating neurotoxicity and BBB impairment in an animal model for HIV-1 encephalitis and alcohol abuse? (Aim 3). Antioxidants and specific signaling inhibitors will be utilized to delineate pathways involved in these effects. We believe that the proposed works are highly significant as they will uncover novel mechanisms involved in the combined effects of HIV-1 and alcohol abuse in the CNS and propose therapeutic approaches based on these investigations. Public Health Relevance: Alcohol is abused by millions of Americans has long lasting toxic effects on the central nervous system. Clinical studies indicated that alcohol dependence has an additive effect on cognitive deficits associated with HIV-1 infection. Current proposal aims to understand mechanisms of combined effects of HIV-1 and alcohol abuse in the brain and to propose neuroprotective therapies.
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1 |
2007 |
Persidsky, Yuri |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Microglial Deactivation and Hiv Dementia: Logical Therapy @ University of Nebraska Medical Center
Mononuclear phagocytes (MP, microglia and perivascular macrophages) serve as targets for productive human immunodeficiency virus type-1 (HIV-1) infection within the central nervous system. Neuroimmune events leading to HIV-1-associated dementia (HAD) are associated with MP secretory products (cellular and viral toxins) produced during HIV-1 encephalitis (HIVE). Laboratory, animal model and postmortem brain tissue studies of HIVE uniformly demonstrate that microglial activation, not the absolute level of virus, is the best correlate for cognitive impairment during HAD. Based on these observations this project will investigate the role of microglial deactivation in pathogenesis of HAD in HIVE SCID model. The established infrastructure of our Center for Neurovirology and Neurodenegerative Disorders (CNND) will be utilized to explore the means to abrogate microglial activation in our experimental animal model of HIVE that reflects the biologic, immune and pathophysiologic effects of HIV-1 replication in brain MP. Specifically, we hypothesize that inhibition of kynurenine pathway in activated microglia leads to a reduction in the neurotoxic potential of these cells and results in cognitive improvement. To test this hypothesis, the following questions will be addressed: 1) What are the contributions of the kynurenine pathway in microglial activation and the consequential neurotoxic activities of immune activated and/or virus activated MP in HAD? 2) Is inhibition of kynurenine pathway in activated microglia a crucial link to improved clinical symptoms? & 3) Does inhibition of kynurenine pathway in activated microglia change neuronal function in the context of HAD neuropathogenesis? We will evaluate effects of MP deactivation via kynurenine pathway on neuro-inflammatory responses, neuronal dysfunction, and cognitive impairment in the HIVE SCID mouse model and correlate these observations with in vitro and ex vivo studies on MP. These works will allow us to investigate novel aspects of neuroimmunology and establish a link between immune and cognitive functions. The potential findings have broad relevance in pathogenesis of a wide range of neurodegenerative disorders beyond HAD. The integration between this project and the others is in serving to best understand the role of microglial immunity in the neuropathogenesis of HIV-1 disease.
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0.961 |
2008 — 2009 |
Persidsky, Yuri |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Macrophage, Blood-Brain Barrier, and Modulation of Neurodegeneration @ University of Nebraska Medical Center
AIDS Virus; ATP[{..}]myosin-light-chain O-phosphotransferase; Acquired brain injury; Acute; Address; Adhesion Molecule; Adhesions; Affect; Animal Model; Animal Models and Related Studies; Anti-Inflammatories; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; Antiretroviral Agents; Appendix; Area; Arts; Assay; Astrocytes; Astrocytus; Astroglia; Attenuated; Bioassay; Biologic Assays; Biological; Biological Assay; Blood; Blood - brain barrier anatomy; Blood leukocyte; Blood monocyte; Blood-Brain Barrier; Body Tissues; Bone Marrow; Brain; Brain Injuries; Brain region; C-C CKR-5 Gene; C-C Chemokine Receptor Type 5 Gene; CC chemokine receptor 1; CC-CKR-5 Gene; CCCKR5 Gene; CCL2; CCL2 gene; CCL5; CCR-5 Gene; CCR5; CCR5 gene; CD183; CD195 Antigen Gene; CD44; CD44 gene; CD8 Cell; CD8 lymphocyte; CD8+ T-Lymphocyte; CD8-Positive Lymphocytes; CD8-Positive T-Lymphocytes; CHEMR13 Gene; CKR-5 Gene; CKR-L2; CKR5 Gene; CMKAR3; CMKBR5 Gene; CRG-2; CXC-R4; CXCL10; CXCL10 gene; CXCL12 protein; CXCR-4; CXCR3; CXCR3 gene; CXCR4; CXCR4 gene; Cell Adhesion Molecules; Cell Body; Cell Communication; Cell Function; Cell Interaction; Cell Locomotion; Cell Migration; Cell Movement; Cell Process; Cell physiology; Cell-to-Cell Interaction; Cell/Tissue, Immunohistochemistry; Cells; Cellular Function; Cellular Matrix; Cellular Migration; Cellular Physiology; Cellular Process; Chemoattractants; Chemokine (C-C Motif) Ligand 5; Chemokine (C-C) Receptor 5 Gene; Chemokine (C-X-C Motif) Ligand 12; Chemotactic Factors; Chemotaxins; Chronic; Co-culture; Cocultivation; Coculture; Coculture Techniques; Collaborations; Complex; Constitution; Cytokines, Chemotactic; Cytoskeletal System; Cytoskeleton; D17S136E; D2S201E; DTP; Data; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Dentate Fascia; Dentate Gyrus; Development; Developmental Therapeutics; Developmental Therapeutics Program; Developmental Therapy; Down-Regulation; Down-Regulation (Physiology); Downregulation; Drug Delivery; Drug Delivery Systems; Drug Packaging; Drug Targeting; Drug Targetings; Drugs; Dysfunction; EC 2.7.1.117; Electrical Resistance; Encephalitis; Encephalon; Encephalons; Endothelial Cells; Evaluation; Extracellular Matrix, Integrins; FB22; FLJ12216; Fascia Dentata; Figs; Figs - dietary; Foundations; Functional disorder; GDCF-2; GDCF-2 HC11; GPR9; Glia; Glial Cells; Grant; Gyrus Dentatus; HC11; HIV-1; HIV-1 Fusion Co-Receptor Gene; HIV-I; HIV1; HM89; HSY3RR; Hemato-Encephalic Barrier; Home; Home environment; Homologous Chemotactic Cytokines; Hortega cell; Human; Human immunodeficiency virus 1; Human, General; IFI10; IHC; INP10; IP-10; IP10; IP10-R; Image; Image Analyses; Image Analysis; Imaging Procedures; Imaging Techniques; Immigrations; Immune; Immunodeficiency Virus Type 1, Human; Immunohistochemistry; Immunohistochemistry Staining Method; Impairment; In Vitro; In element; In-Migration; Indium; Infection; Inflammation, Brain; Inflammatory; Injection of therapeutic agent; Injections; Injury; Integrins; Intercrines; Investigation; KRP; Kolliker's reticulum; LAP3; LCR1; LESTR; Label; Laboratories; Lateral Ventricle of Brain; Lateral Ventricles; Lateral ventricle structure; Leukocytes; Ligands; MCAF; MCP-1; MCP1; MDU3; MGC17164; MGC9434; MLCK; MLCK108; MLCK210; MOB-1; MR Imaging; MR Tomography; MRI; MYLK; MYLK gene; MYLK2; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Mammals, Mice; Mammals, Rodents; Man (Taxonomy); Man, Modern; Marrow leukocyte; Marrow monocyte; Measures; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Medical Imaging, Single Photon Emission Computed Tomography; Medication; Medicine; Methods and Techniques; Methods, Other; Mice; Microglia; Mig-R; MigR; Modeling; Modification; Monomeric G-Proteins; Monomeric GTP-Binding Proteins; Mother Cells; Motility; Motility, Cellular; Murine; Mus; Myosin Kinase; Myosin LCK; Myosin Light Chain Kinase; Myosin Light Chain Kinase, Smooth Muscle and Non-Muscle Isozymes; Myosin Light Polypeptide Kinase; Myosin Regulatory Light-Chain Kinase; Myosin light chain kinase 2, skeletal/cardiac muscle; NMR Imaging; NMR Tomography; NPY3R; NPYR; NPYRL; NPYY3R; Nerve Cells; Nerve Degeneration; Nerve Unit; Nervous; Nervous System, Brain; Neural Cell; Neural Growth; Neural Stem Cell; Neurocyte; Neurodegenerative Diseases; Neurodegenerative Disorders; Neuroglia; Neuroglial Cells; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; Neuron Degeneration; Neuronal Growth; Neuronal Injury; Neurons; Neuropathogenesis; Non-neuronal cell; Nuclear Magnetic Resonance Imaging; Occluding Junctions; Olfactory Bulb; Oligodendrocytes; Oligodendrocytus; Oligodendroglia; Oligodendroglia Cell; P01 Mechanism; P01 Program; Pathway interactions; Pattern; Penetration; Peptide/Protein Chemistry; Permeability; Pgp1; Pharmaceutic Preparations; Pharmaceutical Preparations; Physiologic; Physiological; Physiology; Physiopathology; Pre-B Cell Growth Stimulating Factor; Process; Progenitor Cell Transplantation; Progenitor Cells; Program Project Grant; Program Research Project Grants; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Protein Chemistry; Proteins; RANTES; RANTES Protein, T-Cell; ROC Analysis; Radionuclide Tomography, Single-Photon Emission-Computed; Reaction; Research Program Projects; Resistance, Electric; Reticuloendothelial System, Blood; Reticuloendothelial System, Bone Marrow; Reticuloendothelial System, Leukocytes; Rodent; Rodentia; Rodentias; SCYA2; SCYA5; SCYB10; SDF-1; SDF-1alpha; SIS cytokines; SIS delta; SIS-delta; SISd; SMC-CF; SPECT; SPECT imaging; Science of Medicine; Sdf1 protein; Secondary to; Side; Site; Small G-Proteins; Small GTPases; Small Inducible Cytokine A5; Specificity; Stem Cell Transplantation; Stem cell transplant; Stem cells; Stromal Cell-Derived Factor 1; Structure of dentate gyrus; Structure of olfactory bulb; Subcellular Process; System; System, LOINC Axis 4; T-Cell Specific Protein p288; T8 Cells; T8 Lymphocytes; TCP228; Technics, Imaging; Techniques; Therapeutic; Tight Junctions; Tissues; Tomography, Emission-Computed, Single-Photon; Toxin; Trauma; Vermiform Appendix; Virus; Viruses, General; White Blood Cells; White Cell; Work; Zeugmatography; Zonula Occludens; adherent junction; anti-retroviral; antiretroviral; astrogliosis; base; bioimaging; bioimaging/biomedical imaging; biomedical imaging; brain damage; brain lesion (from injury); brain tissue; cell adhesion protein; cell body (neuron); cell motility; chemoattractant cytokine; chemokine; chemokine receptor; colcothar; complement chemotactic factor; concept; dentate gyrus; design; designing; drug/agent; experiment; experimental research; experimental study; ferric oxide; gIP-10; gene product; gitter cell; gliogenesis; hIRH; human T cell leukemia virus III; human T lymphotropic virus III; image evaluation; imaging; in vivo; injury and repair; injury response; interdisciplinary approach; intracellular skeleton; iron oxide; lateral ventricle; macrophage; mesoglia; microglial cell; microgliocyte; migration; model organism; monocyte; monolayer; mouse model; nano formulation; nano medicine; nano particle; nano toxicology; nanoformulation; nanomedicine; nanoparticle; nanotoxicology; nerve cement; nerve stem cell; neural; neural cell body; neural degeneration; neural progenitor cells; neurodegeneration; neurodegenerative illness; neurogenesis; neuroinflammation; neuron injury; neuron toxicity; neuronal; neuronal cell body; neuronal degeneration; neuronal progenitor; neuronal progenitor cells; neuronal toxicity; neuropathology; neuroprotection; neurotoxicity; new therapeutics; next generation therapeutics; novel therapeutics; olfactory bulb; particle; pathophysiology; pathway; perivascular glial cell; postnatal; prevent; preventing; progenitor; programs; receptors, CCR1; red iron oxide; relating to nervous system; repair; repaired; research study; response; response to injury; rho G-Proteins; rho GTP-Binding Proteins; rho GTPases; rho Protein P21; rho Small GTP-Binding Proteins; smooth muscle myosin light chain kinase; soma; stromal cell-derived factor-1alpha; synapse formation; synaptogenesis; white blood cell; white blood corpuscle
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0.961 |
2009 — 2013 |
Ghorpade, Anuja (co-PI) [⬀] Persidsky, Yuri |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms and Interventions For Methamphetamine and Hiv-1 Induced Cns Injury @ Temple Univ of the Commonwealth
DESCRIPTION (provided by applicant): Methamphetamine (METH), an addictive stimulant has long lasting toxic effects on the central nervous system (CNS). Clinical studies indicated that METH dependence has an additive effect on neuropsychological deficits associated with HIV-1 infection. Oxidative stress, excitotoxicity, BBB impairment and glial cell activation, all have been independently implicated in the mechanisms of METH- and HIV-1-associated neurotoxicity. This proposal will investigate specific mechanisms operative in HIV-1 CNS infection and METH abuse that lead to an overall increase in oxidative stress and NF-kB signaling resulting in impairment of astrocytes and endothelial cell function. We propose that METH-mediated oxidative stress in astrocytes leads to a down regulation excitotoxic amino acid transporter (EAAT) -2, the primary astrocyte glutamate scavenger, while in endothelial cells, such an increase in oxidative stress results in loss of BBB integrity. Indeed, our preliminary data suggest that METH exposure caused ROS generation in astrocytes and human primary BMVEC, diminished EAAT-2 expression, in astrocytes, decreased BBB integrity in vitro that was restored by antioxidant treatment, caused decreased expression/re-distribution of tight junction proteins, enhanced adhesion and migration of monocytes across endothelial monolayers and activated small GTPases in BMVEC that were previously implicated in the BBB injury during HIV-1 encephalitis (HIVE). New preliminary data demonstrated increased permeability of BBB in vivo in animals exposed to METH that was prevented by antioxidant treatment. This proposal will investigate a novel concept of mechanistic commonality, i.e. METH-mediated oxidative stress exerts its cell-specific effects in astrocytes and endothelial cells aggravating injury caused by HIV-1 CNS infection and delineate therapeutic options for these targets using in vivo studies. Using a combination of in vitro assays and METH/HIVE animal model, we will address the following questions: What is the role(s) of enhanced reactive oxygen species, ROS production and NF-kB signaling in diminished expression/function of EAAT-2 in astrocytes? (Aim 1) What are underlying mechanisms of BBB dysfunction and enhanced monocyte adhesion/migration across brain endothelium (via oxidative stress, interference with NF-kB and GTPase signaling)? (Aim 2);and Can therapeutics decreasing oxidative stress and normalizing EAAT-2 function ameliorate BBB dysfunction and neurotoxicity in an animal model for HIVE and METH abuse? (Aim 3) We will address these questions utilizing primary human astrocytes and brain microvascular cells, in vitro BBB models and evaluate combined effects of METH and HIV-1 relevant stimuli on EAAT-2 and BBB function. Antioxidants and specific signaling inhibitors will be utilized to delineate pathways involved in these effects. Our HIVE animal model will be employed to investigate the biological outcomes of these cell-specific mechanisms in cognitive function, BBB damage and neurotoxicity. We believe that the proposed works are highly significant, as they will uncover novel mechanisms involved in the combined effects of HIV-1 and METH in the CNS and propose therapeutic approaches based on these investigations. PUBLIC HEALTH RELEVANCE: Methamphetamine, a highly addictive stimulant abused by millions of Americans has long lasting toxic effects on the central nervous system. Clinical studies indicated that methamphetamine dependence has an addictive effect on cognitive deficits associated with HIV-1 infection. Current proposal aims to understand mechanisms of combined effects of HIV-1 and methamphetamine in the brain and to propose neuroprotective therapies.
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0.928 |
2010 — 2019 |
Persidsky, Yuri |
R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Cns Injury Caused by Hiv-1 and Alcohol: Protective Effects of Cb2 Activation @ Temple Univ of the Commonwealth
DESCRIPTION (provided by applicant): Findings in humans and animal models suggest that alcohol, similar to HIV-1, induces inflammatory processes in the brain leading to neurodegeneration. The causes of HIV-1-associated neurotoxicity are comparable to those mediating alcohol-induced neuronal injury. During the previous period of funding, we demonstrated alcohol-induced impairment of the blood brain barrier (BBB) and neuronal injury and delineated molecular mechanisms of these previously unrecognized phenomena. We showed that alcohol exposure increased neuroinflammation in an animal model of HIV-1 encephalitis (HIVE), confirming that alcohol abuse is an exacerbating factor in HIV-1 brain infection. Diminution of neuroinflammation constitutes a logical approach for prevention of HIV-1 and alcohol mediated neurodegeneration. Agonists of cannabinoid receptor 2 (CB2) possess potent anti-inflammatory and neuroprotective properties. We propose that CB2 activation will attenuate neuronal dysfunction and BBB injury caused by alcohol and HIV-1 via effects on monocytes, brain endothelium, activated microglia and HIV-1 infected macrophages. Relevance of this idea is confirmed by our findings of augmented CB2 expression on brain endothelium in alcoholics, HIVE patients and up-regulated CB2 expression in primary human brain microvascular endothelial cells (BMVEC) by alcohol and cytokines. CB2 agonists protected the barrier against inflammatory and alcohol insults, blocked monocyte migration across BBB and decreased expression of pro-inflammatory factors in activated BMVEC. CB2 agonist decreased leukocyte adhesion to brain endothelium and prevented enhanced BBB permeability in mice with systemic inflammation. Based on these observations, we propose to investigate the therapeutic potential of CB2 activation in diminution of neuroinflammation caused by the combined effects of alcohol and HIV-1. The following questions will be addressed: 1) How do CB2 agonists reverse the effects of alcohol and virus infection on BBB integrity and diminish migration of HIV-1-infected monocytes across the BBB, 2) Can CB2 stimulation ameliorate alcohol and HIV-1-infected macrophage-mediated neurotoxicity, and 3) Can CB2 agonists diminish neuroinflammation, neuronal injury, and BBB dysfunction in an animal model of HIVE and alcohol abuse. The significance of the proposed work is to uncover novel mechanisms underlying the anti-inflammatory potential of CB2 activation that will ameliorate BBB impairment and neuronal dysfunction in the setting of HIV-1 CNS infection and alcohol abuse.
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0.928 |
2012 — 2016 |
Persidsky, Yuri |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Bbb Protection in Hiv Infection: Barrier-Shielding Effects of Parp Inhibition @ Temple Univ of the Commonwealth
DESCRIPTION (provided by applicant): Prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite the introduction of combined antiretroviral therapy. HAND is associated with elevation of pro-inflammatory factors in blood and subsets of activated infected monocytes, both shown to cause blood brain barrier (BBB) impairment that contributes to HAND. Therapeutic strategies that disrupt monocyte migration can slow progression of HIV infection and BBB injury, thereby ameliorating HAND. During the previous period of funding, we focused on studies of (1) molecular mechanisms of BBB injury and (2) anti-inflammatory and barrier protective properties of glycogen synthase kinase (GSK) 3ß inhibition in neuroinflammation driven by HIV infection. We uncovered molecular mechanisms of BBB dysfunction [tight junction (TJ) phosphorylation, CD40/CD40 ligand interactions at BBB and signaling events behind the direct effects of HIV on brain endothelium]. We demonstrated barrier tightening following GSK3ß suppression in brain endothelium due to TJ stabilization. We uncovered potent anti-inflammatory effects of GSK3ß inhibition in brain endothelium (suppression of monocyte migration, diminution of inflammatory factor production, and BBB protection) in vitro and in vivo. GSKß inhibition in monocytes attenuated their adhesion/migration across the BBB, down regulated active integrin expression via suppression of the small GTPase, Rac1, and protected the BBB. Yet, BBB shielding properties or inhibition of monocyte migration/adhesion were not fully attained in vitro or in vivo, suggesting that additional pathways complimentary to GSK3ß are necessary for the restitution of BBB function. In search of such molecules, we turned our attention to poly(ADP-ribose) polymerase-1 (PARP-1) and its inhibitors, recently recognized as anti-inflammatory/immune modulating agents with significant neuroprotective properties. Based upon preliminary data, we propose that PARP inhibition will attenuate BBB injury caused by HIV-1 via effects on monocytes, brain endothelium, activated microglia and HIV-1 infected macrophages. Indeed, preliminary data indicate that PARP suppression in primary human brain microvascular endothelial cells (BMVEC) improved BBB integrity and augmented expression of TJ proteins. PARP inhibitors prevented barrier disruption caused by inflammatory factors, diminished monocyte adhesion/migration across a BBB model, down regulated adhesion molecules/pro-inflammatory molecules and decreased activity of RhoA/Rac1. In monocytes, PARP inhibitors down regulated the active ß-integrin that paralleled RhoA/Rac1 suppression. PARP inhibitors decreased expression of pro-inflammatory molecules and diminished HIV replication in human macrophages. Although the modulatory effects of PARP inhibitors on immune cells have been studied to some extent, nothing is known about their effects in the setting of HIV CNS infection. PARP inhibitors have now reached the stage of clinical testing for cancer treatment, assuring quick translation to therapy of immune/inflammatory disorders.
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0.928 |
2015 — 2019 |
Jordan-Sciutto, Kelly L [⬀] Persidsky, Yuri |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Secoisolariciresinol Diglucoside to Mitigate Inflammation and Toxicity in Hand @ University of Pennsylvania
? DESCRIPTION (provided by applicant): Clinical intervention over the past two decades has changed HIV infection from a death sentence to a chronic disease. Despite pharmacological management of HIV-infection, approximately 50% of patients continue to present with neurologic impairment termed HIV-associated neurocognitive disorders (HAND), with persistent neuroinflammation and oxidative tissue damage. Current approaches to mitigate HAND have focused on agents targeting a single cellular function, which may limit their efficacy in a complex multisystem disease. Therefore, novel, pluripotent agents capable of acting simultaneously on diverse pathways and cellular processes may present an opportunity in the short and long term management of HIV. Thus, brain penetrant agents capable of controlling oxidative and inflammatory processes with minimal toxicity over prolonged administration to humans are attractive candidates in mitigating or preventing such effects associated with HAND. Our group has been investigating protective properties of secoisolariciresinol diglucoside (SDG), the main bioactive lignan phenolic in wholegrain flaxseed. Dietary SDG boosts endogenous antioxidant defenses in murine tissues, and exhibits potent anti-inflammatory and antioxidant activity in several tissues including the CNS. SDG and its metabolites can cross the blood-brain barrier (BBB) and enter brain tissues, making it an attractive candidate for mitigation of HIV-induced neurotoxicity. We therefore hypothesize that SDG, as a pluripotent agent, will mitigate HIV-associated neurotoxicity by reducing BBB damage, neuroinflammation, and oxidative stress. SDG is safe and well tolerated in humans and findings from numerous recent clinical trials enhance the translational aspect of our proposed study, which aims to provide novel insights into the usefulness of SDG, and to elucidate its mechanisms of action. Using in vitro modeling, Aims 1-3 will determine the effects of SDG on BBB damage, leukocyte trafficking across the BBB, microglial activation and neurotoxicity induced by HIV infection, and will elucidate mechanisms that underlie the efficacy of SDG as an agent that reduces neuroinflammation and oxidative stress. Aim 4 will investigate the ability of SDG to mitigate BBB damage, neuroinflammation, oxidative stress and neurotoxicity in the humanized mouse model of HIV infection, the huNSG-HIV mouse. Together, these studies will provide evidence to support SDG as adjunctive treatment for management of HAND.
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0.961 |
2016 — 2020 |
Persidsky, Yuri |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Novel Cb2 Agonists Shield Brain From Hiv Infection and Alcohol Exposure @ Temple Univ of the Commonwealth
? DESCRIPTION (provided by applicant): Despite combined antiretroviral therapy, HIV-1 associated neurocognitive disorders (HAND) remain highly prevalent in infected patients. HAND progression is associated with chronic inflammatory responses outside and inside of the central nervous system (CNS) driven by low levels of HIV replication, monocyte/macrophage activation, inefficient immune responses and compromise of the blood brain barrier (BBB). Inflammatory mediators and engagement of immune cells migrating into the CNS result in BBB injury. Alcohol misuse (common co-morbidity in HIV infected patients) accelerates HIV progression and HAND. Data obtained in humans and animal models suggest that alcohol promotes neuroinflammation and BBB injury. Therefore, interventions diminishing HIV replication and decreasing chronic inflammation could ameliorate HAND in the setting of alcohol abuse. Cannabinoid receptor 2 (CB2) agonists possess potent anti-inflammatory effects, protect the BBB and suppress HIV infection in macrophages. Although the published studies strongly suggest that CB2 activation may represent a promising novel therapeutic target for HIV infection and HAND, what is missing is the availability of CB2 agonists with optimal pharmacological properties (oral bioavailability, appropriate pharmacokinetics) and absence of major toxicity as tested in relevant `humanized' models of HIV infection and neuroinflammation. Using complimentary expertise in CB2 receptor pharmacology/toxicology (NIAAA intramural research program) and modeling of HIV infection in vitro and in vivo (Temple University) we propose to test a set of novel, highly selective and orall available CB2 agonists assuring quick translation toward clinical application for the treatment of HIV infection. We will first identify selective CB2 agonists with improved pharmacological properties and toxicology profile, and then test their ability to decrease HIV replication in human macrophages, to diminish migration of HIV infected monocytes and to protect the BBB in the setting of alcohol exposure. Lastly, we will evaluate the best CB2 compounds in a `humanized' animal model of HIV infection. This proposal brings together research expertise that will address key HIV and alcohol based research questions that would not otherwise be possible.
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0.928 |
2016 — 2020 |
Persidsky, Yuri Rogers, Thomas J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Hiv-Induced Neuroinflammation Associated With Opiod Abuse and Tobacco Smoke @ Temple Univ of the Commonwealth
DESCRIPTION (provided by applicant): Opiate drug abuse is a critical contributor to the global AIDS epidemic, and over a third of HIV infections in the U.S. can be linked to intravenous drug abuse. Recent estimates suggest that almost 20% of intravenous drug abusers are infected with HIV. Tobacco smoking is prevalent in HIV-infected patients, and is very common among intravenous drug abusers. Importantly, smoking is strongly associated with a number of non-AIDS conditions, including chronic obstructive lung disease (COPD), and this chronic inflammatory disease may contribute to the development of neuroinflammation associated with HIV infection. However, there is very little known about the combined effects of tobacco smoke and chronic opioid administration on the development of inflammatory responses, and even less known about the effects of these clinically relevant drugs on the development of neurodegeneration following HIV infection. We describe preliminary data which shows that the inflammatory response is both quantitatively and qualitatively distinct following the combination of tobacco and opiate administration. We propose to conduct experiments using humanized mice to examine the combined effects of chronic tobacco smoke exposure with and without chronic administration of morphine on the development of HIV-induced neuroinflammation. Our published and preliminary data show that the blood-brain barrier is a target for the effects of opiates and/or tobacco, as well as the inflammatory activity of monocytes and macrophages. We propose to investigate the mechanistic basis for the combined effects of these drug treatments on these cell populations. We believe the proposed studies will provide highly novel information about the effects of morphine and tobacco smoke on HIV-associated neurodegeneration in a clinically relevant immunological context.
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0.928 |
2018 |
Persidsky, Yuri Rogers, Thomas J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Hiv-Induced Neuroinflammation Associated With Opioid Abuse and Tobacco Smoke @ Temple Univ of the Commonwealth
DESCRIPTION (provided by applicant): Opiate drug abuse is a critical contributor to the global AIDS epidemic, and over a third of HIV infections in the U.S. can be linked to intravenous drug abuse. Recent estimates suggest that almost 20% of intravenous drug abusers are infected with HIV. Tobacco smoking is prevalent in HIV-infected patients, and is very common among intravenous drug abusers. Importantly, smoking is strongly associated with a number of non-AIDS conditions, including chronic obstructive lung disease (COPD), and this chronic inflammatory disease may contribute to the development of neuroinflammation associated with HIV infection. However, there is very little known about the combined effects of tobacco smoke and chronic opioid administration on the development of inflammatory responses, and even less known about the effects of these clinically relevant drugs on the development of neurodegeneration following HIV infection. We describe preliminary data which shows that the inflammatory response is both quantitatively and qualitatively distinct following the combination of tobacco and opiate administration. We propose to conduct experiments using humanized mice to examine the combined effects of chronic tobacco smoke exposure with and without chronic administration of morphine on the development of HIV-induced neuroinflammation. Our published and preliminary data show that the blood-brain barrier is a target for the effects of opiates and/or tobacco, as well as the inflammatory activity of monocytes and macrophages. We propose to investigate the mechanistic basis for the combined effects of these drug treatments on these cell populations. We believe the proposed studies will provide highly novel information about the effects of morphine and tobacco smoke on HIV-associated neurodegeneration in a clinically relevant immunological context.
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0.928 |
2018 — 2020 |
Picone, Joseph [⬀] Obeid, Iyad (co-PI) [⬀] Persidsky, Yuri Farkas, Tunde |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Mri: High Performance Digital Pathology Using Big Data and Machine Learning
This project, developing a digital imaging system, aims to automatically characterize an enormous archive of digital images from a pathology lab. Based on open source programming language packages and using deep learning technologies, the effort entails developing software that will automatically annotate and classify these images. Thus the system consists of an annotated archive tool for high performance digital pathology involving digital images from pathology slides produced in clinical operations. This tool, presently unavailable, enables observation, annotation, and classification of images from tissues in pathology slides in order to create a very large data base that may be analyzed with algorithms that are designed to process and interpret the image data. By applying state of the art machine learning, the effort is expected to generate a sustainable facility to rapidly collect large amounts of data automatically. This facility enables deep learning systems to systematically address many operational challenges, such as ingestion of large, complex images.
Broader Impacts: The instrumentation provides a useful technology capability. The work builds on the researchers' history of providing unencumbered resources for fields including human language technology and neuroscience. Several large, comprehensive databases of pathology slides will be released in an unencumbered manner; no comparable databases currently exist in terms of the quantity of data proposed. The urban setting of the project, as well as the diverse nature of the institution's client population, make it ideal for collecting this type of clinical data. A new generation of healthcare professionals will be trained using these resources to validate their knowledge in the longer term.
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1 |
2018 — 2021 |
Persidsky, Yuri |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Blood Brain Barrier Injury in Hiv Infection Complicated by Diabetes: Mechanisms and Protective Strategies Preventing Cognitive Impairment @ Temple Univ of the Commonwealth
Despite combined antiretroviral therapy (ART) achieving efficient HIV replication control, HIV- associated neurocognitive disorders (HAND) continue to be highly prevalent in HIV-infected patients. One of the explanations could be constant compromise of blood brain barrier (BBB) driven by chronic inflammatory responses documented in HIV-infected individuals even with well-controlled virus replication yet with HAND progression. Chronic neuroimmune activation is present in ART-treated patients as indicated by elevated levels of soluble inflammatory factors in the cerebrospinal fluid and blood. Diabetes mellitus (DM) is a well-known comorbidity of HAND in HIV-infected patients. BBB dysfunction has been linked recently to dementia development, specifically in DM patients. BBB injury has been documented in animal models of diabetes showing memory deficits and was associated with dysfunction of brain pericytes supporting endothelial cells. Taking together clinical and experimental data, BBB injury exists both in HIV and DM, likely contributing to cognitive decline. However, its extent, exact cellular targets and mechanisms are largely unknown. We propose that cognitive impairment in HIV- infected individuals is mediated by BBB injury that is further aggravated by metabolic alterations associated with DM causing HAND. Preliminary data support this idea showing elevated glucose levels correlated with increased BBB permeability, cognitive impairment, microglia activation and loss of pericytes in animal models for DM types 1 and 2. We found a decrease in pericyte coverage and expression of tight junction proteins in human brain tissues from HIV patients with DM and evidence of HAND. Using our in vitro BBB models, we demonstrated diminution of barrier integrity, enhanced monocyte adhesion, changes in cytoskeleton and overexpression of adhesion molecules after exposure to HIV and DM-relevant stimuli. We hypothesize that prevention of BBB compromise in DM/HIV will diminish neurocognitive decline independently of tight glucose control. We will identify biomarkers of such BBB injury, correlate with barrier damage and cognitive decline, define signaling pathways associated with BBB injury in DM/HIV and test novel treatment approaches. We will study the contribution of DM- and HIV- mimicking conditions on cognition and BBB injury in cross-validating experiments using well- established in vitro systems (co-culture of human primary brain microvascular endothelial cells/primary human brain pericytes), functional assays, animal models of DM types 1 and 2 combined with HIV brain exposure and `humanized' NSG mice with chronic HIV infection and diabetes. Results of such studies will open opportunities for very much needed individualized treatment for HAND.
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0.928 |
2020 — 2021 |
Persidsky, Yuri Rogers, Thomas J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Inflammation Associated With Hiv Infection: Role of Receptor Cross-Talk @ Temple Univ of the Commonwealth
Abstract: Opiate drug abuse is a critical contributor to the global AIDS epidemic, and over a third of HIV infections in the U.S. can be linked to intravenous drug abuse. Recent estimates suggest that almost 20% of intravenous drug abusers are infected with HIV. HIV-associated neuropathy remains a clinically significant issue for patients infected with HIV, even in the current era of anti-retroviral therapy. In addition, HIV-infected opiate abusers demonstrate a more severe neuropathy than non-opiate abusers, and the basis for the greater neuropathy remains uncertain. In this application, we propose that HIV infection in the brain results in an inflammatory response, which promotes the production of inflammatory chemokines, leading to the activation of the respective chemokine receptors, resulting in the cross-desensitization of opioid receptors. The consequence of this set of events is an elevated sensitivity to pain stimuli. We propose to test these processes using mouse models to evaluate the influence of HIV gp120 in the induction of neuroinflammation, including the associated neuropathic pain. Our proposed studies will also attempt to address the ability of morphine to attenuate the development of this pain response. We also propose to confirm these studies through the analysis of an authentic HIV infection using a humanized mouse model. We believe the results from these studies will greatly enhance our understanding of the mechanisms which contribute to the development of neuroinflammation in HIV-infected subjects, including those who are opiate abusers.
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0.928 |