Drug abuse and HIV-associated pulmonary vascular injury

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Project Summary This administrative supplement proposal is to examine if the circulating endothelial-derived small extracellular vesicles (EVs) can be leveraged as a non-invasive biomarker of pulmonary vascular dysfunction using a novel microfluidic chip-based platform. Lately, EVs have emerged as important mediators in cell-cell communication, and the role of alterations in their cargo has been implicated in various diseases, including pulmonary hypertension (PH). However, to allow for rapid integration into clinical practice, there remains a need for an inexpensive, user-friendly approach to the quantitative analysis of EV-linked putative biomarkers. So, in this supplement, we intend to leverage a novel microfluidics-based bioanalytical platform to overcome these technological barriers and the procedure complexity of isolating EVs required for screening large patient cohorts. Premature aging is one of the important factors contributing to the increased prevalence of cardiopulmonary diseases in people living with HIV (PWH) and pulmonary vascular endothelial cells have been reported to be highly senescent in PH. Using a highly sensitive nanoengineered chip-based bioanalytic platform for the detection of EC-EVs and a targeted proteomics approach, we propose to test the central hypothesis that the higher numbers of circulating endothelial-derived small EVs (EC-EVs) in PWH carry pro- aging factors that are associated with an increased prevalence of HIV associated PH. This supplement request is within the scope of an active parent NIH award on HIV-PH, and the innovative microfluidic approach is expected to expedite the analysis of a selective sub-population of plasma-derived EVs with increased sensitivity, specificity, and efficiency. This state-of-the-art technology will also allow for future customization of new putative EV-linked biomarkers in larger clinical studies. Furthermore, this technology may be adapted in the future to also identify markers of other vascular pathologies such as frailty and cerebrovascular and renal pathologies, which are very common in PWH.