Biology subjects

Lallai, V.

Publications and source records attributed to Lallai, V..

3 recordsLinked to original sources

bioRxiv2024

AI Derived Therapeutic Development for the Treatment of Opioid Use Disorder

The opioid epidemic has led to a devastating loss of life nationwide. Of those dependent on opioids, many individuals desire to quit or reduce use, but their efforts are often unsuccessful given the powerful reinforcing properties associated with opioid drugs, especially fentanyl given its high potency and speed of onset. Here, we developed a novel theraputic based on a newly developed artificial intelligence (AI)-based platform, which was rationally designed to identify markers of dysregulation from human drug user postmortem brain tissue. The GATC-021 compound was synthesized and validated with in vitro screening for target specificity. Thereafter, GATC-021 was examined for its effectiveness in modulating opioid dependence with an animal model of addiction. We found that GATC-021 substantially reduced fentanyl intake in both male and female rats, as assessed with intravenous self-administration. However, given drug soluability challenges, additional studies are needed to better develop drug formulations to permit translation into clinical populations more effectively. Taken together, these findings validate our AI-based platform for novel therapeutic development with a polypharmacy approach and further support the effectiveness of such target modulation as a promising therapeutic approach for those suffering from opioid use disorder.

neuroscience↗

bioRxiv2023

Exomap1 mouse: a transgenic model for in vivo studies of exosome biology

Exosomes are small extracellular vesicles (sEVs) of [~]30-150 nm in diameter that have the same topology as the cell, are enriched in selected exosome cargo proteins, and play important roles in health and disease. To address large unanswered questions regarding exosome biology in vivo, we created the exomap1 transgenic mouse model. In response to Cre recombinase, exomap1 mice express HsCD81mNG, a fusion protein between human CD81, the most highly enriched exosome protein yet described, and the bright green fluorescent protein mNeonGreen. As expected, cell type-specific expression of Cre induced the cell type-specific expression of HsCD81mNG in diverse cell types, correctly localized HsCD81mNG to the plasma membrane, and selectively loaded HsCD81mNG into secreted vesicles that have the size ([~]80 nm), topology (outside out), and content (presence of mouse exosome markers) of exosomes. Furthermore, mouse cells expressing HsCD81mNG released HsCD81mNG-marked exosomes into blood and other biofluids. Using high-resolution, single-exosome analysis by quantitative single molecule localization microscopy, we show here that that hepatocytes contribute [~]15% of the blood exosome population whereas neurons contribute <1% of blood exosomes. These estimates of cell type-specific contributions to blood EV population are consistent with the porosity of liver sinusoidal endothelial cells to particles of [~]50-300 nm in diameter, as well as with the impermeability of blood-brain and blood-neuron barriers to particles >5 nm in size. Taken together, these results establish the exomap1 mouse as a useful tool for in vivo studies of exosome biology, and for mapping cell type-specific contributions to biofluid exosome populations. In addition, our data confirm that CD81 is a highly-specific marker for exosomes and is not enriched in the larger microvesicle class of EVs.

cell biology↗

bioRxiv2021

Disruption of VGLUT1 in cholinergic medial habenula projections increases nicotine self-administration

Cholinergic projections from the medial habenula (MHb) to the interpeduncular nucleus (IPN) have been studied for their complex contributions to nicotine addiction and have been implicated in nicotine reinforcement, aversion, and withdrawal. While it has been established that MHb cholinergic projections co-release glutamate, no direct evidence has demonstrated a role for this specific glutamate projection in nicotine consumption. In the present study, a novel floxed Slc17a7 (VGLUT1) mouse was generated and used to create conditional knockout (cKO) mice that lack VGLUT1 in MHb cholinergic neurons. Histochemical approaches and optogenetics-assisted electrophysiology were used to validate the disruption of VGLUT1 from cholinergic MHb to IPN projections. The mice displayed no gross phenotypic abnormalities and exhibited normal exploratory and locomotor behavior in the open-field assay. However, the loss of VGLUT1-mediated glutamate co-release led to increased nicotine self-administration. These findings indicate that glutamate co-release from ventral MHb cholinergic neurons opposes nicotine consumption and provide additional support for targeting this synapse to develop potential treatments to nicotine addiction.

neuroscience↗