Antiretroviral Therapy Impacts Autophagy in Astrocytes, and May Contribute to HIV Associated Neurocognitive Disorders
Antiretroviral Therapy Impacts Autophagy in Astrocytes, and May Contribute to HIV Associated Neurocognitive Disorders
批准号:
10477626
负责人:
Laura Cheney
金额:
$19.44万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-08-18 至 2026-07-31
关键词:
Anti-Retroviral AgentsAstrocytesAutophagocytosisAutopsyBrainCRISPR/Cas technologyCell physiologyCellsClinicalCommunicable DiseasesConfocal MicroscopyDataDevelopmentEmploymentEnzyme-Linked Immunosorbent AssayExposure toFlow CytometryFoundationsFunctional disorderGenus HippocampusGlutamatesGoalsHIVHIV InfectionsHIV-associated neurocognitive disorderHomeostasisHumanImmunofluorescence ImmunologicLearningMeasuresMediatingMedical centerMedicineMembrane PotentialsMentorsMicroscopyMitochondriaModelingNeurodegenerative DisordersNeuropathogenesisPathogenesisPathogenicityPathologyPersonsPharmaceutical PreparationsPharmacologyPlaguePrincipal InvestigatorProcessProductionProgram DevelopmentProteinsProteolysisProteomicsPublishingQuality ControlQuality of lifeQuantitative Reverse Transcriptase PCRRNARegimenReporterResearchRespirationRoleSpecificityStimulusSupporting CellTechniquesTenofovirToxic effectTransmission Electron MicroscopyViremiaWestern BlottingWorkantiretroviral therapybasebrain cellbrain tissuecareer developmentcell typecollegecomorbidityemtricitabineexperienceexperimental studyextracellularinhibition of autophagyinnovationinstructorknock-downlight microscopymitochondrial autophagymortalityneuroAIDSnormal agingnoveloverexpressionpreventreceptorresponseskillstherapeutic targettherapy developmenttooluptake
中文摘要
项目总结/摘要
该提案提出了一个为期4年的研究职业发展计划,重点是研究
在HIV相关神经认知障碍(HAND)的背景下,
对HAND发病机制的理解,目的是确定HAND治疗的靶点。的
候选人目前是Montefiore Medical的传染病和病理学讲师
中心/阿尔伯特·爱因斯坦医学院。该提案建立在候选人以前的艾滋病毒研究基础上,
通过整合两个新的专业领域的临床经验,由她的导师,伯曼博士和
博士Cuervo。拟议的实验和教学工作将为切尼博士提供技能,
她过渡到独立作为主要研究者在neuroHIV和macroautophagy的十字路口。
尽管用抗逆转录病毒药物控制了病毒血症,但仍有相当数量的HIV感染者(PWH)发展为HAND
治疗(ART)。对HAND的潜在因素的不完全理解阻碍了治疗HAND的努力。
发展数据表明,失调的自噬可能有助于HAND,但仍有很多工作要做。
特别是星形胶质细胞。维持星形胶质细胞的稳态是至关重要的,因为它们是主要的
支持大脑的细胞,为中枢神经系统执行许多重要功能。由于星形胶质细胞依赖于自噬
由于星形胶质细胞自噬的异常调节可能导致细胞内环境的改变,因此了解星形胶质细胞自噬的异常调节尤为重要,
手这一建议的基础是基于我们发表的数据,这些数据表明,
在原代人星形胶质细胞中的自噬,其由以下常用处方方案治疗引起:
替诺福韦、恩曲他滨和雷特格韦(ART)。本提案的目的是:1.描述ART诱导
人星形胶质细胞中自噬的变化,2.表征经处理的人星形胶质细胞中的选择性自噬
艺术,3。定义作为ART治疗结果的星形胶质细胞特异性功能的变化,
自噬的变化。这些目标将扩大对威尔斯亲王医院人力资源发展的理解,
ART时代,最终目标是确定缓解HAND的治疗靶点。
英文摘要
Project Summary/Abstract
This proposal presents a 4 year research career development program focused on the study of
macroautophagy (autophagy) in the context of HIV associated neurocognitive disorders (HAND) to increase
the understanding of HAND pathogenesis with the goal of identifying targets for treatment of HAND. The
candidate is currently an Instructor of Infectious Diseases and of Pathology at Montefiore Medical
Center/Albert Einstein College of Medicine. The proposal builds on the candidate’s previous HIV research and
clinical experiences by integrating two new domains of expertise, overseen by her mentors, Dr. Berman and
Dr. Cuervo. The proposed experiments and didactic work will provide Dr. Cheney with the skill sets to enable
her transition to independence as a Principal Investigator at the crossroads of neuroHIV and macroautophagy.
A significant number of people with HIV (PWH) develop HAND despite control of viremia with antiretroviral
therapy (ART). Efforts to treat HAND are hindered by an incomplete understanding of the factors underlying its
development. Data suggest that dysregulated autophagy may contribute to HAND, but much remains to be
understood, specifically in astrocytes. It is essential to maintain astrocyte homeostasis because they are major
support cells of the brain, performing many vital functions for the CNS. As astrocytes rely on autophagy for
homeostasis, it is particularly important to understand dysregulated astrocyte autophagy as it may contribute to
HAND. The foundation for this proposal is based on our published data demonstrating an inhibitory effect on
autophagy in primary human astrocytes resulting from treatment with a commonly prescribed regimen of
Tenofovir, Emtricitabine and Raltegravir (ART). The aims of this proposal are to: 1. Characterize ART induced
changes in autophagy in human astrocytes, 2. Characterize selective autophagy in human astrocytes treated
with ART, and 3. Define changes in astrocyte-specific functions as a result of ART treatment, and correlate
with changes in autophagy. These aims will expand the understanding of HAND development in PWH in the
ART era, with the ultimate objective of identifying therapeutic targets with which to mitigate HAND.
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会议论文
Antiretroviral Therapy Impacts Autophagy in Astrocytes, and May Contribute to HIV Associated Neurocognitive Disorders
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批准号:10686274
-
项目类别:
-
资助金额:$19.44万
-
财政年份:2022
-
负责人:Laura Cheney
-
依托单位:
国内基金
海外基金
Ascl1介导Wnt/beta-catenin通路在TLE海马硬化中反应性Astrocytes异常增生的作用及调控机制
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批准号:31760279
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项目类别:地区科学基金项目
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资助金额:35.0万元
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批准年份:2017
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负责人:丁银秀
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依托单位: