PROJECT ABSTRACT The objectives of the parent R21 grant are: 1) to directly modulate the lncRNA LASI levels in airway epithelial cells by gain- and loss-of-function studies; and 2) to identify the mechanisms by which LASI modulates inflammatory responses by analyzing its potential as the precursor for microRNAs or microproteins, or as the sponge that binds the microRNAs. Thus, the three major focuses in the parent R21 are lncRNA LASI, inflammatory responses and HIV-1 infection. Here, we want to broaden the scope of these three major focuses by also evaluating the potential of lncRNA LASI to mitigate neuroinflammation in a mouse model of Alzheimer’s disease (AD) as well as a comorbidity model of HIV and AD which is emerging as a major health problem in recent years. In the preliminary studies, LASI transcript levels in the temporal cortical regions in autopsied brain tissues of patients with AD were highly upregulated and correlated with the increased neuropathologies and neuroinflammation compared to tissues from unaffected control subjects. More importantly, ablation of LASI expression directly modulates the cellular inflammatory responses. Together these data thus suggest that LASI lncRNA transcripts are an important modulator of neuroinflammatory responses, and the dysregulated expression of LASI results in the exacerbated neuroinflammation and AD-associated neurodegeneration. Strikingly, the AD-related pathologies are highly prevalent among HIV-infected population and not much is known about the underlying molecular mechanisms. Here, we propose to further develop upon our preliminary studies and determine whether HIV-infection further exacerbates the AD-associated neuroinflammation and determine the role of LASI therein. Studies in Aim 1 will interrogate the role of LASI by employing genetic editing in CNS cell culture models of AD and HIV infection, In Specific Aim 2, molecular entities that interact with LASI to tamper the neuroinflammation will be investigated. Role of miRNA-150-5p that potentially interacts with LASI transcripts and their association with HIV- or LPS-induced neuroinflammation will be investigated. In-vivo targeting of LASI will be tested for evaluating its role in modulating the neuroinflammatory pathologies using the transgenic mouse models of AD pathologies and HIV infection. Since, we plan to test the effect of lncRNA LASI directly in a mouse model of HIV (iTAT-Tg) and AD (3xTg-AD) and address three key questions in HIV/AD research, i.e., HIV and AD comorbidity, neuroinflammation, and AD-associated pathologies including Aβ plaques and neurofibrillary tangles, this administrative supplement request is directly related to Alzheimer’s disease and related dementias (ADRD). If targeting the lncRNA LASI is successful in mitigating neuroinflammation and amyloid plaques/tangles, it may be translated to the clinical studies in future.