of the administrative supplement The objectives of the parent R01 grant are 1) to develop and evaluate the transport, delivery, release on demand and efficacy of nanoformulation containing cannabinoid receptor modulators to activate latent HIV infection, eradicate HIV and protect from HIV/cannabinoid-induced neuronal deficits using an in-vitro BBB-HIV infection cannabinoid model, 2) to evaluate the in vivo efficacy of the developed nanocarrier in HIVE SCID cannabinoid mouse model, and 3) to monitor the neurobehavioral modulations induced by nanoformulation in HIVE SCID cannabinoid mouse model. Thus the three major focuses in the parent R01 are the HIV, magneto- electric nanoparticle (MENP)-based drug delivery and the cannabinoid pathway. Here we want to broaden the scope of these three major focuses by also evaluating the potential of cannabinoid system for therapy during the comorbidity of HIV and Alzheimer?s disease (AD) which is emerging as a major health problem in recent years. Following the introduction of HAART, many HIV patients live longer and thus enter an age when the risk of developing AD increases exponentially. So far, the apoE4 allele is the strongest genetic risk factor identified in sporadic AD patients, and there is also a strong association between apoE4 and the rate of HIV-1 disease progression, suggesting a strong relationship between HIV infection and AD pathogenesis. This is not surprising given the fact that exposure to HIV particles and HIV proteins can directly or indirectly modulate the amyloid and Tau proteins, the two hallmark features of AD. Also, HIV-infected elders have a higher rate of meeting criteria for mild cognitive impairment (MCI). Therefore, we hypothesize a synergistic effect of the comorbidity of HIV and AD on the common neuropathological features such as A?, tau, neurodegeneration, and synaptic loss. Further, treatment with cannabinoid activators through the developed nanoformulation will mitigate these neuropathological features. We will test this hypothesis by generating 3xTg-AD/iTAT bigenic mice (+/- doxycycline) and compare the results with 3xTg-AD and iTAT (+/- Dox) single transgenic lines.
In specific aim 1, using MENP technology, we will evaluate the role of cannabinoid CB1 and CB2 receptor agonists and antagonists on the subventricular zone (SVZ) and subgranular zone (SGZ) adult neurogenesis as well as levels of A? and hyperphosphorylated tau. In the specific aim 2, we will evaluate the role of ECS on the dendritic spine density and number of synapses and correlate with learning and memory skills. Since we plan to test the cannabinoid system directly in a mouse model of HIV (iTAT) and AD (3xTg-AD) and address three key questions in HIV/AD research, i.e., HIV and AD comorbidity, cannabinoid multitarget pathway and efficient brain penetration, this administrative supplement request is directly related to Alzheimer?s disease and related dementias (ADRD). If the liposomal-MENP drug delivery in this HIV/AD comorbidity mouse model is successful, it may also be extended to other neurological diseases in future studies.

Public Health Relevance

This administrative supplement application is in response to PA-18-591 and NIH notice, NOT-AG-18-039 in relation to extending the active R01 projects to Alzheimer?s disease and related dementia (ADRD) research. In recent years, comorbidity of HIV infection and Alzheimer?s disease is increasing which is expected to have synergistic effects on neuropathology Here we want to test whether endocannabinoid pathway that has multitarget effects could reduce A? and tau, and also make new neurons and more synaptic connections thereby prevent loss of cognition in a comorbid model of HIV and Alzheimer?s disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA040537-05S1
Application #
9858066
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Tsai, Shang-Yi Anne
Project Start
2015-09-30
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Florida International University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
071298814
City
Miami
State
FL
Country
United States
Zip Code
33199
Vashist, Arti; Kaushik, Ajeet; Vashist, Atul et al. (2018) Nanogels as potential drug nanocarriers for CNS drug delivery. Drug Discov Today 23:1436-1443
Sagar, Vidya; Nair, Madhavan (2018) Near-infrared biophotonics-based nanodrug release systems and their potential application for neuro-disorders. Expert Opin Drug Deliv 15:137-152
Vashist, Arti; Kaushik, Ajeet; Vashist, Atul et al. (2018) Advances in Carbon Nanotubes-Hydrogel Hybrids in Nanomedicine for Therapeutics. Adv Healthc Mater 7:e1701213
Jayant, Rahul Dev; Tiwari, Sneham; Atluri, Venkata et al. (2018) Multifunctional Nanotherapeutics for the Treatment of neuroAIDS in Drug Abusers. Sci Rep 8:12991
Kaushik, Ajeet; Jayant, Rahul Dev; Bhardwaj, Vinay et al. (2018) Personalized nanomedicine for CNS diseases. Drug Discov Today 23:1007-1015
Jayant, Rahul Dev; Atluri, Venkata S R; Tiwari, Sneham et al. (2017) Novel nanoformulation to mitigate co-effects of drugs of abuse and HIV-1 infection: towards the treatment of NeuroAIDS. J Neurovirol 23:603-614
Kaushik, Ajeet; Tiwari, Sneham; Jayant, Rahul D et al. (2017) Electrochemical Biosensors for Early Stage Zika Diagnostics. Trends Biotechnol 35:308-317
Vashist, Arti; Kaushik, Ajeet; Alexis, Kayla et al. (2017) Bioresponsive Injectable Hydrogels for On-demand Drug Release and Tissue Engineering. Curr Pharm Des 23:3595-3602
Kaushik, Ajeet; Nikkhah-Moshaie, Roozbeh; Sinha, Raju et al. (2017) Investigation of ac-magnetic field stimulated nanoelectroporation of magneto-electric nano-drug-carrier inside CNS cells. Sci Rep 7:45663
Sagar, Vidya; Pilakka-Kanthikeel, S; Martinez, Paola C et al. (2017) Common gene-network signature of different neurological disorders and their potential implications to neuroAIDS. PLoS One 12:e0181642

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