Enhanced APOE2 Expression into Brain for Therapeutic Strategy for Alzheimer's Disease
增强 APOE2 在大脑中的表达,用于阿尔茨海默病的治疗策略
基本信息
- 批准号:10514954
- 负责人:
- 金额:$ 19.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-15 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AgingAlzheimer&aposs DiseaseAnti-Inflammatory AgentsAwardBiodistributionBiologicalBiological MarkersBirthBrainBrain-Derived Neurotrophic FactorCannabidiolCell ProliferationCognitiveComplementary DNACurcuminDetectionDrug Delivery SystemsDrug KineticsEnzyme KineticsEnzyme-Linked Immunosorbent AssayEquipmentFundingGenesGoalsHigh Pressure Liquid ChromatographyHippocampus (Brain)InflammatoryLearningLifeLiquid substanceMemoryMessenger RNAMetabolismNeuraxisNeurodegenerative DisordersNeuronsNucleic AcidsOrganPharmaceutical PreparationsPharmacologyPolymerase Chain ReactionPreventionProteinsQuercetinRNAReaderResearchResearch PersonnelResveratrolRisk FactorsScienceSynapsesSynaptic plasticitySystemTherapeuticTimeUniversitiesabsorptionbasecytokinecytotoxicitydesigndrug discoverygenetic analysisin vivoinstrumentinstrumentationmRNA Expressionnanoparticleneurogenesisneuroinflammationnon-viral gene deliverysynaptic functionsynergism
项目摘要
SUMMARY:
Neuroinflammation is one of the major risk factor which leads to the progression of neurodegenerative disorders.
The birth of new neurons within the hippocampal region of the central nervous system continues throughout life,
and the amount of neurogenesis correlates closely with the hippocampal functions of learning and memory.
Neuroinflammation alone inhibits neurogenesis and that inflammatory blockade with an anti-inflammatory agent
restores neurogenesis. Anti-inflammatory (AI) drug reduces the expression of various inflammatory cytokines
and increased synapse number. Drugs such as curcumin, resveratrol, quercetin and cannabidiol from natural
origin have demonstrated both anti-inflammatory activity and neurogenesis. ApoE2, VGF and BDNF have been
found useful in maintaining cell proliferation, neuronal function and synaptic plasticity throughout life. Moreover,
it has been shown that an increased level of ApoE2, VGF, and BDNF in the brain is associated with neurogenesis
and cell proliferation. Therefore combination of AI and ApoE2 or BDNF would synergistically enhance
neurogenesis and synaptic functions. The long-term goal of the requested supplement award is to design a
non-viral gene delivery carrier for efficient delivery of drugs, shAPOE4, mRNA encoding APOE2, pAPOE2,
BDNF and other genes to brain for prevention and treatment of aging-related cognitive decile including AD. The
requested supplement equipment award would strengthen the science of drug discovery in the following ways:
(1).Determination of AI drugs in delivery matrix and biological fluids as well as in vivo pharmacokinetics and
biodistributions of drugs by HPLC: The HPLC system would help us to quantify the amount of AI drugs entrapped
in nanoparticles, and study in vivo the pharmacokinetics and biodistribution of drugs in various organs. (2).
Quantification of target genes in different matrices by Quantitative Real Time Polymerase chain reaction (qRT-
PCR), thermocycler, and multi-mode microplate reader: The qRT-PCR provides fast and high-throughput reliable
detection and quantification of target genes in different matrices. The qRT-PCR instrument will enable us to
quantify the changes in mRNA expression as a function of time. The thermocycler will allow the conversion of
RNA to cDNA which will further be quantified in the qRT-PCR. BioTek™ Synergy™ HTX Multi-Mode Microplate
Reader will be used for various applications in our lab ranging from nucleic acid quantification, protein
quantification, enzyme kinetics, biomarker quantification, ELISAs, genetic analysis, cell proliferation, cytotoxicity,
and drug absorption and metabolism. The requested fund ($190,981) to procure the above equipment items
would help investigate delivery of drugs, mRNA, pAPOE2, shAPOE4, BDNF and other nucleic acids through
nanoparticle-based delivery systems. We anticipate that the requested equipment will significantly contribute to
the field of drug discovery for AD pharmacological therapy. Thus, these proposed research equipment would
have high impact in developing drug and nucleic acid based therapy for AD. In addition, the requested equipment
would also be available to conduct quality research to other investigators in the department and university.
总结:
神经炎症是导致神经退行性疾病进展的主要危险因素之一。
在中枢神经系统的海马区域内,新神经元的诞生贯穿一生,
神经发生的数量与海马的学习记忆功能密切相关。
神经炎症单独抑制神经发生,
恢复神经发生。抗炎(AI)药物减少各种炎症细胞因子的表达
突触数量增加姜黄素、白藜芦醇、槲皮素和大麻二酚等药物,
已经证明了抗炎活性和神经发生。ApoE 2、VGF和BDNF已被
在维持细胞增殖、神经元功能和突触可塑性方面有用。此外,委员会认为,
已经表明,脑中ApoE 2、VGF和BDNF水平的增加与神经发生有关,
和细胞增殖。因此,AI和ApoE 2或BDNF的组合将协同增强
神经发生和突触功能。所要求的补充奖的长期目标是设计一个
用于有效递送药物的非病毒基因递送载体,shAPOE 4,编码APOE 2的mRNA,pAPOE 2,
脑源性神经营养因子和其他基因对大脑的影响,用于预防和治疗包括AD在内的与衰老相关的认知障碍。的
所要求的补充设备奖将在以下方面加强药物发现科学:
(1).递送基质和生物流体中AI药物的测定以及体内药代动力学和
HPLC法测定药物的生物分布:HPLC系统将帮助我们定量测定包埋的AI药物的量
在纳米颗粒中,并在体内研究药物在各种器官中的药代动力学和生物分布。(二)、
通过定量真实的时间聚合酶链反应(qRT-PCR)定量不同基质中的靶基因
PCR)、热循环仪和多模式酶标仪:qRT-PCR提供快速、高通量、可靠的
不同基质中靶基因的检测和定量。qRT-PCR仪器将使我们能够
定量mRNA表达随时间的变化。热循环仪将允许以下物质的转化:
RNA至cDNA,其将在qRT-PCR中进一步定量。BioTek™ Synergy™ HTX多模式微孔板
阅读器将用于我们实验室的各种应用,从核酸定量,蛋白质
定量、酶动力学、生物标志物定量、ELISA、遗传分析、细胞增殖、细胞毒性,
以及药物吸收和代谢。采购上述设备所需资金(190 981美元)
将有助于研究药物,mRNA,pAPOE 2,shAPOE 4,BDNF和其他核酸的传递,
基于纳米颗粒的递送系统。我们预计,所要求的设备将大大有助于
AD药物治疗的药物发现领域。因此,这些拟议的研究设备将
在开发用于AD的药物和基于核酸的疗法中具有高影响。此外,所要求的设备
也将提供给部门和大学的其他研究人员进行高质量的研究。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A review of the tortuous path of nonviral gene delivery and recent progress.
- DOI:10.1016/j.ijbiomac.2021.05.192
- 发表时间:2021-07-31
- 期刊:
- 影响因子:8.2
- 作者:Sharma D;Arora S;Singh J;Layek B
- 通讯作者:Layek B
Brain-targeted delivery of losartan through functionalized liposomal nanoparticles for management of neurogenic hypertension.
通过功能化脂质体纳米颗粒脑靶向递送氯沙坦用于治疗神经源性高血压。
- DOI:10.1016/j.ijpharm.2023.122841
- 发表时间:2023
- 期刊:
- 影响因子:5.8
- 作者:Lamptey,RichardNiiLante;Sun,Chengwen;Singh,Jagdish
- 通讯作者:Singh,Jagdish
In vitro and in vivo optimization of liposomal nanoparticles based brain targeted vgf gene therapy.
- DOI:10.1016/j.ijpharm.2021.121095
- 发表时间:2021-10-25
- 期刊:
- 影响因子:5.8
- 作者:Arora S;Singh J
- 通讯作者:Singh J
Design and Validation of Liposomal ApoE2 Gene Delivery System to Evade Blood-Brain Barrier for Effective Treatment of Alzheimer's Disease.
- DOI:10.1021/acs.molpharmaceut.0c00461
- 发表时间:2021-02-01
- 期刊:
- 影响因子:4.9
- 作者:Arora, Sanjay;Layek, Buddhadev;Singh, Jagdish
- 通讯作者:Singh, Jagdish
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{{ truncateString('Takahisa Kanekiyo', 18)}}的其他基金
Neuronal ABCA7 loss of function and Alzheimer’s disease
神经元 ABCA7 功能丧失与阿尔茨海默病
- 批准号:
10629715 - 财政年份:2023
- 资助金额:
$ 19.1万 - 项目类别:
Therapeutic Strategy to Treat Alzheimer's Disease by VGF Delivery into Brain
通过将 VGF 输送至大脑来治疗阿尔茨海默病的治疗策略
- 批准号:
10738951 - 财政年份:2023
- 资助金额:
$ 19.1万 - 项目类别:
Enhanced APOE2 Expression into Brain for Therapeutic Strategy for Alzheimer's Disease
增强 APOE2 在大脑中的表达,用于阿尔茨海默病的治疗策略
- 批准号:
10208342 - 财政年份:2021
- 资助金额:
$ 19.1万 - 项目类别:
Pathogenic mechanisms of ABCA7 in Alzheimer's disease
ABCA7在阿尔茨海默病中的发病机制
- 批准号:
9221000 - 财政年份:2017
- 资助金额:
$ 19.1万 - 项目类别: