Cerebral organoid and ipsc derived microglia: modeling of HIV and methamphetamine CO-morbidity
Active Project Grant Awarded Last action
- Award ID
- R01DA056906
- Recipient
-
Board Of Regents Of The University Of Nebraska UEI G15AG3BLLMH4 Part of Board Of Regents Of University Of Nebraska
- Awarding agency
-
National Institute on Drug Abuse
National Institutes of Health, Department of Health and Human Services
- Obligated
- $3,677,993
Award facts
- Assistance listing
- 93.279 Drug Use and Addiction Research Programs
- Completion date 84% complete
- Place of performance
- Omaha, NE 68198, USA
Award details come from USAspending.gov.
Description
- Abstract
- An estimated ~1.3 million adults and adolescents are living with human immunodeficiency virus (HIV) infection in the USA of which 15% of them undiagnosed. The initiation of combination antiretroviral therapy (cart) has transformed aids from a fatal illness into a chronic and manageable disease. The presence of HIV infected microglia and macrophage reservoirs in the central nervous system (CNS) and variable penetration of anti- retroviral drugs across the blood brain barrier after cart are likely factors for the persistence of HIV associated neurocognitive disorder (hand). Drugs of abuse such as the potent psychostimulant methamphetamine (meth) that is abused by an estimated 30 million people in the world further minimize the efficacy of cart and in conjunction with HIV exacerbate CNS pathology. Thus, significant GAP in knowledge in the field is to better understand the neuropathogenesis and the etiology of clinical outcomes observed in HIV+ patient's dependent on meth abuse. The current grant proposal focuses on developing a human induced pluripotent stem cell based cerebral organoid model to investigate underlying brain dysfunction during HIV/meth interaction. Cerebral organoids are 3-dimensional "mini brains" that can self-organize and recapitulate many milestone events seen in in vivo brain development. Our recent study on generating a novel organoid model with the feasibility in controlling the microglia ratio and microenvironment of organoid formation to recapitulate changes in brain functions under various conditions (e.g. virus and viral infection-induced inflammation and synaptic pruning) makes this model ideal for our proposed studies. The central hypothesis of this proposal is that meth in conjunction with HIV causes significant neuronal damage. The combination of microglia-containing cerebral organoid model, extracellular vesicle biology, single-cell RNA-sequencing, crispr/CAS9-mediated gene editing will decipher novel intercellular and molecular mechanisms and pathways that underlie abnormalities in neuronal functions and connectivity caused by HIV infection. We will investigate this hypothesis under three specific aims: specific aim 1 will examine neuronal function, synaptic and mitochondrial perturbations during HIV/meth interactions in 3D microglia-containing cerebral organoid model; specific aim 2 will investigate the role of extracellular vesicles in microglial organoids treated under HIV/meth conditions; and specific aim 3 will characterize the molecular mechanisms underlying HIV infection-induced neuronal injury and further evaluate our microglial organoid model as a reliable tool to identify molecular signatures of hand. Our proposed experiments will decipher molecular mechanisms, novel signaling events and molecular partners underlying the neuronal injury in hand. Through the series of the experiments we aim to present an easily scalable and reproducible model to study hand pathogenesis. The data obtained from these studies can be used to design novel therapeutics to control HIV infection.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $500,639 | |
| Amendment | $520,609 | |
| Amendment | $495,815 | |
| Amendment | $531,074 | |
| Amendment | $531,074 | |
| Amendment | $549,391 | |
| Original award | $549,391 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Rutgers, The State University | $191,540 | |
| Rutgers The State University Of New Jersey | $191,540 | |
| Rutgers The State University Of New Jersey | $225,466 |
Quick answers
Who received award R01DA056906?
R01DA056906 was awarded to Board Of Regents Of The University Of Nebraska by National Institute on Drug Abuse (National Institutes of Health) on September 1, 2022.
How much is award R01DA056906 worth?
$3,677,993 has been obligated on R01DA056906.
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