课题基金 / 基金详情

Develop and evaluate efficacy of nanoformulated siBeclin1 delivered intranasally to eliminate HIV in brain

Develop and evaluate efficacy of nanoformulated siBeclin1 delivered intranasally to eliminate HIV in brain
开发并评估鼻内递送的纳米制剂 siBeclin1 消除大脑中 HIV 的功效
批准号:
9893032
负责人:
NAZIRA EL-HAGE
金额:
$22.46万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-03-13 至 2022-02-28
关键词:
Acquired Immunodeficiency SyndromeAddressAffectAlanineAlanine TransaminaseAnti-Retroviral AgentsAntibodiesAreaAstrocytesAttenuatedAutophagocytosisBasal GangliaBehavior TherapyBehavioralBiodistributionBiological AssayBloodBlood Urea NitrogenBody WeightBrainCD34 geneCalcium BindingCalcium ionCardiacCell NucleusCellsChemistryDNADevelopmentDiseaseDrug KineticsEnzyme-Linked Immunosorbent AssayFemaleFreezingFunding OpportunitiesFutureGlial Fibrillary Acidic ProteinGliosisHIVHIV InfectionsHIV antiretroviralHIV therapyHIV-1Hand StrengthHealthHeartHematoxylin and Eosin Staining MethodHepatotoxicityHippocampus (Brain)HistologicHistologyImmune responseImmunofluorescence ImmunologicIndividualInflammatoryInflammatory ResponseIntravenousKidneyKineticsLabelLearningLiquid ChromatographyLiquid substanceLiverLungMannoseMeasuresMembraneMethodologyMicrogliaMicrotubule-Associated Protein 2Microtubule-Associated ProteinsMorphologyMotorMusNational Institute of Mental HealthNeuraxisNeuronsNitrogenOrganPathologicPathologyPathway interactionsPerfusionPharmaceutical PreparationsPharmacotherapyPolymerase Chain ReactionProteinsPublic HealthPuncture procedureQuantitative Reverse Transcriptase PCRRNARegimenResearchResearch PriorityReverse TranscriptionSafetySensoryShort-Term MemorySmall Interfering RNAStainsTestingTherapeuticTherapeutic AgentsTimeToxic effectTreatment EfficacyTubeViralVirus ReplicationWestern Blottingantiretroviral therapybasebrain cellchemokinecytokinecytotoxicitydesigndosageglial activationhumanized mouseinsightmacrophagemalemanmemory processmorris water mazenanoformulationnephrotoxicityneuropathologynext generationnonhuman primatenovelnovel therapeutic interventionobject recognitionparticlepreservationresponsespatial memorytandem mass spectrometry

项目摘要

项目成果

NAZIRA EL-HAGE的其他基金

相似基金

相关文献

中文摘要
翻译
项目总结
英文摘要
PROJECT SUMMARY Develop and Evaluate the Efficacy of Nanoformulated siBeclin1 Delivered Intranasally to Eliminate HIV in the Brain. The overall hypothesis is that small interfering (si) RNAs targeting the autophagy pathway can act as a synergistic therapeutic agent with antiretroviral drugs to eliminate central nervous system (CNS) HIV reservoirs and viral associated inflammatory responses in perivascular macrophages, microglia [1,2] and astrocytes [3]. To this end, we will synthesize a siBeclin1 siRNA- polyethylenimine (PEI) polyplex [4] to facilitate intranasal delivery to the brain [4]. The nanoformulated siBeclin1 which transiently diminishes expression of host protein Beclin1, will be tested for its efficacy in eliminating brain cell HIV reservoirs in humanized mice. Efficient intranasal delivery (Figure 1), deployment of mannose decorated particles (Figure 2) and quantitative measures of viral replication will be employed (Figure 3). In the first two sub aims (a &b) of Aim 1, we will quantitatively measure the pharmacokinetics and bio-distribution of siBeclin1 in brain, lung, heart, liver and kidney by reverse transcription polymerase chain reaction (RT-PCR) and liquid chromatography- tandem mass spectrometry (LC-MS/MS) methodologies. Since cell toxicity is a problem encountered with many antiretroviral therapies, in Aim 1c, morphological changes due to cytotoxicity in the brain will be assessed by histology using Hematoxylin and eosin (H&E) and Nissl staining to detect for neuronal damages. Followed by immunohistochemical labeling of neuronal nuclei (NeuN) or microtubule-associated protein 2 (MAP2) to assess for the surviving neuronal cells in the brain. The cell marker, ionized calcium binding adaptor molecule 1 (Iba-1) or CD68 specific for microglia and glial fibrillary acidic protein (GFAP) specific for astrocytes will be used to detect Glial activation (gliosis). Inflammatory responses will be measured by cytokine and chemokine membrane-based antibody arrays and confirmed by colorimetric sandwich enzyme-linked immunosorbent assay (ELISA). Chemistry analysis on the levels of blood urea nitrogen and alanine transaminase activity, will indicate toxicity of the kidneys and liver, respectively. In Aim 2a, we will determine the efficacy of the nanoformulated siBeclin1 on the different aspects of CNS pathology induced by HIV ± antiretroviral drugs including (1) viral replication (measured by PCR-based assays); (2) secretion of immune responses (measured by ELISA-based assays); (3) glial activation and (4) neuronal health (measured by histological and immunohistochemical based assays). Special emphasis will be placed on the hippocampus and the basal ganglia as these regions are most affected by HIV disease and are critical for brain development, learning and memory processes and sensory motor function. In aim 2b, behavioral changes elicited by HIV infection alone or in combination with antiretroviral drug regimen ± nanoformulated siBeclin1 will be assessed using the novel object recognition test as an indicator of short-term memory and the Morris water maze to measure spatial memory. The sensory motor test will be assessed by using the Rota-rod, grip-strength and horizontal bar.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Function of astrocytes autophagy in brain homeostasis and opioid-induced maladaptive behavior and addiction, in the context of HIV
  • 批准号:
    10619748
  • 项目类别:
  • 资助金额:
    $36.08万
  • 财政年份:
    2023
  • 负责人:
    NAZIRA EL-HAGE
  • 依托单位:
Impact of μ-opioid receptor (MOR) splice variant interactions with the chemokine receptor CCR5 in the context of morphine and HIV-1 entry inhibitor therapy
  • 批准号:
    9308938
  • 项目类别:
  • 资助金额:
    $18.13万
  • 财政年份:
    2016
  • 负责人:
    NAZIRA EL-HAGE
  • 依托单位:
Impact of μ-opioid receptor (MOR) splice variant interactions with the chemokine receptor CCR5 in the context of morphine and HIV-1 entry inhibitor therapy
  • 批准号:
    9064917
  • 项目类别:
  • 资助金额:
    $18.13万
  • 财政年份:
    2016
  • 负责人:
    NAZIRA EL-HAGE
  • 依托单位:
Role of Autophagy in Microglia-induced NeuroAIDS in Substance Abuse
  • 批准号:
    8823758
  • 项目类别:
  • 资助金额:
    $35.71万
  • 财政年份:
    2014
  • 负责人:
    NAZIRA EL-HAGE
  • 依托单位:
海外基金