LncRNA in Alzheimer's Disease-Associated Neuroinflammation and Neurodegeneration

项目摘要 母公司R21赠款的目标是：1)直接调节呼吸道上皮细胞中的lncRNA LASI水平 2)确定LASI的调节机制。 通过分析其作为MicroRNAs或MicroProtein前体的潜力，或作为 结合microRNA的海绵。因此，亲本R21中的三个主要焦点是lncRNA LASI， 炎症反应和HIV-1感染。在这里，我们想扩大这三个主要焦点的范围 通过评估lncRNA LASI在减轻阿尔茨海默病小鼠模型神经炎症中的潜力 疾病(AD)以及艾滋病毒和AD的共病模型，这正在成为#年的一个主要健康问题 最近几年。在初步研究中，尸检大脑颞叶皮质区域的LASI转录本水平 阿尔茨海默病患者的组织高度上调，并与神经病理和 神经炎症与未受影响的对照受试者的组织进行比较。更重要的是，消融LASI 表达直接调节细胞的炎症反应。因此，这些数据表明，LASI LncRNA转录本是神经炎性反应的重要调节器，而调控失调的 LASI的表达导致神经炎症加重和AD相关的神经变性。 值得注意的是，与AD相关的病理在HIV感染人群中非常普遍，人们对此知之甚少 关于潜在的分子机制。在这里，我们建议在初步研究的基础上进一步发展 并确定HIV感染是否会进一步加剧AD相关的神经炎症，并确定 LASI在其中的作用。AIM 1的研究将通过在中枢神经系统中使用基因编辑来询问LASI的作用 AD和HIV感染的细胞培养模型，特定目的2，与LASI相互作用的分子实体 将对神经炎症进行调查。MiRNA-150-5p可能与LASI转录本相互作用的作用 并将调查它们与艾滋病毒或内毒素诱导的神经炎症的关系。LASI的体内靶向研究 将使用转基因小鼠进行测试，以评估其在调节神经炎性病理中的作用 阿尔茨海默病病理模型和HIV感染。因为，我们计划直接在小鼠身上测试lncRNA lasi的效果。 HIV(ITAT-TG)和AD(3xTg-AD)的模型，并解决艾滋病毒/AD研究中的三个关键问题，即艾滋病毒和 AD合并症、神经炎症和AD相关病理包括Aβ斑块和神经原纤维 唐尔斯，这项行政补充请求与阿尔茨海默病和相关痴呆直接相关 (ADRD)。如果靶向lncRNA LASI在减轻神经炎症和淀粉样斑块/缠结方面是成功的， 将来有可能转化为临床研究。

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.