Team Science for MultiScale Data Mining and Functional Validation of Single-Cell Opioid Responses in the Context of HIV

University Of California-Irvine, Irvine CA

Investigators

Abstract

With approximately 296 million people (5.8% of the global population aged 15–64) having used drugs at least once, the world is facing an unprecedented opioid epidemic. Chronic opioid exposure can lead to long-term brain function changes and opioid use disorder (OUD). Concurrently, despite advancements in treatment that have transformed HIV into a manageable chronic disease, evidence shows that opioid use in HIV-infected individuals can further weaken immune function and exacerbate HIV-related central nervous system (CNS) impairments. To unravel the intricate interplay between these conditions, several SCORCH data generation and analysis centers have been funded to generate large-scale molecular profiling data at single-nuclei resolution, allowing the revelation of cell-type-specific molecular alterations due to chronic opioid exposure and/or HIV infection. However, the driving forces behind these molecular changes and their underlying regulatory mechanisms remain elusive, hindering our understanding of these factors and limiting the development of effective therapeutic strategies. To address this gap, we propose the DMFV-SCORCH project, an interdisciplinary initiative aimed at uncovering multi-scale dysregulations resulting from HIV and OUD through population-scale single-nuclei sequencing data, and validating our findings with advanced genomic assays. Specifically, we aim to identify intra- and inter-cellular dysregulations that lead to transcriptomic alterations and brain dysfunctions in OUD and HIV. We will address three key questions: 1) Which cell types are significantly affected, and what epigenetic changes lead to differentially expressed genes (DEGs) in these cell types? 2) Within a cell, what alterations in the gene regulatory network (GRN) and 3D chromatin conformation contribute to the DEGs? 3) How do regulatory changes in the CNS microenvironment, via cell-cell communications (CCC), impact DEGs? To achieve this goal, we will: 1) develop advanced Artificial Intelligence (AI) methods for data mining on SCORCH and atlas-level public CNS single-nuclei sequencing data, highlighting multi-scale dysregulations due to HIV/OUD; and 2) conduct functional validations through advanced genomic assays, such as epigenetic and transcriptomic manipulations via CRISPR followed by snRNA-seq (e.g., CROP-seq) and high-throughput screenings using massively parallel reporter assays (MPRA). Collectively, our examination of the interrelationships among genetic, epigenetic, transcriptional, network, and inter-cellular dysregulations will offer a robust translational approach to unravel the independent and synergistic mechanisms of OUD and HIV.