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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH062962-12
Application #
8440302
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Colosi, Deborah
Project Start
2000-12-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
12
Fiscal Year
2013
Total Cost
$353,400
Indirect Cost
$125,400
Name
University of California San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Valera, Elvira; Masliah, Eliezer (2016) Combination therapies: The next logical Step for the treatment of synucleinopathies? Mov Disord 31:225-34
Fields, Jerel A; Overk, Cassia; Adame, Anthony et al. (2016) Neuroprotective effects of the immunomodulatory drug FK506 in a model of HIV1-gp120 neurotoxicity. J Neuroinflammation 13:120
Valera, Elvira; Masliah, Eliezer (2016) Therapeutic approaches in Parkinson's disease and related disorders. J Neurochem 139 Suppl 1:346-352
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Overk, C R; Rockenstein, E; Florio, J et al. (2015) Differential calcium alterations in animal models of neurodegenerative disease: Reversal by FK506. Neuroscience 310:549-60
Zhang, Dongxian; Lee, Brian; Nutter, Anthony et al. (2015) Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid. J Neurochem 133:898-908
Eleuteri, Simona; Di Giovanni, Saviana; Rockenstein, Edward et al. (2015) Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer's disease. Neurobiol Dis 74:144-57

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