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Mechanisms of Neuroprotection in HIV Encephalitis
1 December 2000 - 31 March 2017
NATIONAL INSTITUTE OF MENTAL HEALTH
Total Funding: $ 3,757,746
DESCRIPTION (provided by applicant): Modern treatments with highly active antiretroviral therapy (HAART) regimens result in HIV suppression and immune recovery, however the prevalence of HIV-Associated Neurocognitive Disorders (HAND) and neurodegeneration has remained the same or increased. During the previous period of funding we showed that abnormal activation of cyclin dependent kinase-5 (CDK5) plays a key role in HIV. We also demonstrated that abnormal activation of CDK5 promotes neurodegeneration via accumulation of TAU and collapsin response mediator protein-2 (CRMP2), a novel target in HAND. Remarkably, knockdown of CDK5 reduced the deficits in a gp120 tg model. For the renewal the main objectives will be;a) to better understand the cellular mechanisms through which HIV proteins promote nucleo-cytoplasmic translocation and pathological activation of CDK5 leading to TAU/CRMP2 mediated neurotoxicity, and b) to determine if TAU reduction or CDK5 inhibition with a new class of CDK5 inhibitors that penetrate the BBB is neuroprotective in preclinical models of HIV neurotoxicity. Our central hypothesis is that HIV proteins such as trans-activator of transcription (Tat) and gp120 modulate cell cycle regulators and interfere with the subcellular localization of CDK5. CDK5 nucleo-cytoplasmic translocation could promote the neurotoxic phosphorylation of CDK5 substrates such as TAU and CRMP2. Therefore strategies to modulate CDK5 or reduce TAU might represent novel therapeutic interventions for HAND. For this purpose we propose the following Aims: Aim 1: To elucidate the role of CDK5 translocation and TAU/CRMP2 phosphorylation in the cellular mechanisms of HIV neurotoxicity. Aim 2: To determine whether TAU reduction in vivo ameliorates the neurodegenerative and behavioral deficits in tg rodent models of HIV neurotoxicity. Aim 3: To evaluate the neuroprotective effects of novel and more specific CDK5 inhibitor which reduce TAU/CRMP2 phosphorylation in tg models of HIV neurotoxicity. This new direction represents a natural extension from the previous period of funding and provides a new avenue that might lead to the development of a novel class of HIV neuroprotective drugs. ! PUBLIC HEALTH RELEVANCE: Modern treatments with highly active antiretroviral therapy regimens result in HIV suppression and immune recovery, however the prevalence of HIV-Associated Neurocognitive Disorders (HAND) and neurodegeneration has not decreased, therefore, the management of HAND requires new therapies in order to address the toxic effects of HIV. For this project we propose to better understand the cellular mechanisms through which HIV proteins promote nucleo-cytoplasmic translocation and pathological activation of CDK5 leading to TAU/CRMP2 mediated neurotoxicity, and to determine whether TAU reduction or CDK5 inhibition is neuroprotective in preclinical models of HIV neurotoxicity.
25 Resulting Publications
Paula Desplats; Wilmar Dumaop; David Smith; Anthony Adame; Ian Everall; Scott Letendre; Ronald Ellis; Mariana Cherner; Igor Grant; Eliezer MasliahNeurology 2013;80(15):1415-23.
Jerel Fields; Wilmar Dumaop; Edward Rockenstein; Michael Mante; Brian Spencer; Igor Grant; Ron Ellis; Scott Letendre; Christina Patrick; Anthony Adame; et al.Journal of neurovirology 2013;19(1):89-101.
Virawudh Soontornniyomkij; David J Moore; Ben Gouaux; Benchawanna Soontornniyomkij; Erick T Tatro; Anya Umlauf; Eliezer Masliah; Andrew J Levine; Elyse J Singer; Harry V Vinters; et al.AIDS (London, England) 2012;26(18):2327-35.
Virawudh Soontornniyomkij; Benchawanna Soontornniyomkij; David J Moore; Ben Gouaux; Eliezer Masliah; Spencer Tung; Harry V Vinters; Igor Grant; Cristian L AchimJournal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 2012;7(3):579-90.
Virawudh Soontornniyomkij; Ian P Everall; David J Moore; Ben Gouaux; Erick T Tatro; Vadim Gospodarev; Eliezer Masliah; Nicole S Yin; Harry V Vinters; Cristian L AchimJournal of neurovirology 2012;18(4):313-22.
E-M Ratai; S Pilkenton; J He; R Fell; J P Bombardier; C-G Joo; M R Lentz; W-K Kim; T H Burdo; P Autissier; et al.Journal of medical primatology 2011;40(5):300-9.
Eva-Maria Ratai; Lakshmanan Annamalai; Tricia Burdo; Chan-Gyu Joo; Jeffrey P Bombardier; Robert Fell; Reza Hakimelahi; Julian He; Margaret R Lentz; Jennifer Campbell; et al.Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine 2011;66(3):625-34.
Amy D Paulino; Kiren Ubhi; Edward Rockenstein; Anthony Adame; Leslie Crews; Scott Letendre; Ronald Ellis; Ian P Everall; Igor Grant; Eliezer MasliahJournal of neurovirology 2011;17(4):327-40.
L Crews; C Patrick; A Adame; E Rockenstein; E MasliahCell death & disease 2011;2():e120.
Erick T Tatro; Erick R Scott; Timothy B Nguyen; Shahid Salaria; Sugato Banerjee; David J Moore; Eliezer Masliah; Cristian L Achim; Ian P EverallPloS one 2010;5(4):e10337.
Eva-Maria Ratai; Jeffrey P Bombardier; Chan-Gyu Joo; Lakshmanan Annamalai; Tricia H Burdo; Jennifer Campbell; Robert Fell; Reza Hakimelahi; Julian He; Patrick Autissier; et al.PloS one 2010;5(5):e10523.
Italo Mocchetti; Alessia Bachis; Eliezer MasliahJournal of neuroscience research 2008;86(2):243-55.
Britta Hult; Gursharan Chana; Eliezer Masliah; Ian EverallInternational review of psychiatry (Abingdon, England) 2008;20(1):3-13.
John P Norman; Seth W Perry; Holly M Reynolds; Michelle Kiebala; Karen L De Mesy Bentley; Margarita Trejo; David J Volsky; Sanjay B Maggirwar; Stephen Dewhurst; Eliezer Masliah; et al.PloS one 2008;3(11):e3731.
Ronald Kuczenski; Ian P Everall; Leslie Crews; Anthony Adame; Igor Grant; Eliezer MasliahExperimental neurology 2007;207(1):42-51.
Edward Rockenstein; Magdalena Torrance; Anthony Adame; Michael Mante; Pazit Bar-on; John B Rose; Leslie Crews; Eliezer Masliah
Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer's disease are associated with reduced amyloid precursor protein phosphorylation.The Journal of neuroscience : the official journal of the Society for Neuroscience 2007;27(8):1981-91.
Scott L Letendre; Steven P Woods; Ronald J Ellis; J Hampton Atkinson; Eliezer Masliah; Geoffrey van den Brande; Janis Durelle; Igor Grant; Ian Everall;AIDS (London, England) 2006;20(14):1885-8.
Matthew J Bellizzi; Shao-Ming Lu; Eliezer Masliah; Harris A GelbardThe Journal of clinical investigation 2005;115(11):3185-92.
Dianne Langford; Rosemary Hurford; Makoto Hashimoto; Murat Digicaylioglu; Eliezer MasliahBMC neuroscience 2005;6():8.
Eliezer Masliah; Eleanor S Roberts; Dianne Langford; Ian Everall; Leslie Crews; Anthony Adame; Edward Rockenstein; Howard S FoxJournal of neuroimmunology 2004;157(1-2):163-75.
Dianne Langford; Aline Grigorian; Rosemary Hurford; Anthony Adame; Ronald J Ellis; Lawrence Hansen; Eliezer MasliahJournal of neuropathology and experimental neurology 2004;63(10):1038-47.
Helen Samland; Salvador Huitron-Resendiz; Eliezer Masliah; Jose Criado; Steven J Henriksen; Iain L CampbellJournal of neuroscience research 2003;73(2):176-87.
T D Langford; S L Letendre; G J Larrea; E MasliahBrain pathology (Zurich, Switzerland) 2003;13(2):195-210.
Dianne Langford; Eliezer MasliahJournal of neurovirology 2002;8(6):625-38.
Ian P Everall; Christopher Bell; Margaret Mallory; Dianne Langford; Anthony Adame; Edward Rockestein; Eliezer MasliahMolecular and cellular neurosciences 2002;21(3):493-501.
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1 August 1995 - 31 January 2003
FOGARTY INTERNATIONAL CENTER
Total Funding: $ 156,000
Mehrdad Alirezaei; Debbie D Watry; Claudia F Flynn; William B Kiosses; Eliezer Masliah; Bryan R G Williams; Marcus Kaul; Stuart A Lipton; Howard S FoxThe Journal of neuroscience : the official journal of the Society for Neuroscience 2007;27(41):11047-55.
I Vincent; G Jicha; M Rosado; D W DicksonThe Journal of neuroscience : the official journal of the Society for Neuroscience 1997;17(10):3588-98.
Rukhsana Sultana; D Allan ButterfieldNeurochemical research 2007;32(4-5):655-62.
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