A novel therapeutic approach for Alzheimer Disease (AD)
阿尔茨海默病(AD)的新治疗方法
基本信息
- 批准号:10740016
- 负责人:
- 金额:$ 39.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AMD3100APP-PS1Adenovirus VectorAdenovirusesAdverse effectsAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease therapyAnabolismAnimal ModelAnimalsAutologousBioenergeticsBiological AssayBloodBlood CirculationBlood flowBone MarrowBrainBrain DiseasesCSF3 geneCell SurvivalCell physiologyCellsChronicCirculationCollaborationsConsumptionDataDementiaDevelopmentDiseaseDown-RegulationElderlyElectron TransportEnzymesErythrocytesGenesGeneticGenetic DiseasesGenomeGenome StabilityHelper-Inducer T-LymphocyteHematopoietic Stem Cell MobilizationHematopoietic stem cellsHomeostasisHumanImpaired cognitionImpairmentInterventionLeftLiverMammalian CellMemory LossMetabolicMetabolic dysfunctionMetabolismMethodsMitochondriaMusMuscleNerve DegenerationNicotinamide adenine dinucleotideOrganPathologyPathway interactionsPeripheralPhysiologicalPlasmaProcessProductionQuantitative Reverse Transcriptase PCRRespirationRoleSerotypingSubcutaneous InjectionsSystemTestingTransgenesWestern Blottingadult neurogenesisbehavioral phenotypingbiological adaptation to stressbrain tissuecell typecellular transductioncofactorexperimental studyfunctional disabilitygene therapygenetic approachhematopoietic differentiationhuman modelin vivoinnovationmetabolic phenotypemetabolomicsmouse modelnervous system disorderneuron lossnicotinamide phosphoribosyltransferasenovelnovel therapeutic interventionoverexpressionperipheral bloodvectorβ-amyloid burden
项目摘要
Project Summary
Alzheimer's Disease (AD) is a chronic neurological disorder causing cellular and organismal metabolic
dysfunction, progressive memory decline and cognitive impairments. Nicotinamide adenine dinucleotide (NAD+)
is an essential metabolite that is involved in cellular bioenergetics, genomic stability, mitochondrial homeostasis,
adaptive stress responses, and cell survival. A growing body of evidence indicates that NAD+ decline is
accompanied with progression of AD. In mammalian cells, the salvage pathway of NAD+ biosynthesis is the
predominant pathway for NAD+ biosynthesis, where nicotinamide phosphoribosyltransferase (Nampt) is the rate-
limiting enzyme. Thus, physiological means to systematically maintain elevated NAD+ levels to augment cellular
metabolic activity in the brain may represent an efficient anti-AD intervention. Red blood cells (RBCs),
differentiated from hematopoietic stem/progenitor cells (HSPCs) in bone marrow (BM) and release to blood
circulation system after maturation, are the most abundant cell type in whole body, and thus, increase in NAD+
synthesis in these cells using genetic interventions may provide a physiological means for systematic and
sustained elevation of NAD+ in whole body through the circulation system. Here we developed an innovative
approach, i.e., using serotype helper-dependent adenovirus (HD-Ad5) to overexpress NAMPT in the RBCs
following in vivo transduction of autologous HSPCs in mouse model. We hypothesize that Nampt
overexpression (OE) in RBCs provides systematic and sustained NAD+ production to increase metabolic activity,
and counteract NAD+ decline in AD and ameliorate AD conditions. To test our hypothesis, we propose the
following two specific aims. Aim 1 will test that Nampt OE in RBCs can systematically elevates NAD+ levels in
metabolically active organs and enhances metabolic activity at cellular and organismal levels. We will transduce
HSPCs by HD-Ad5-Nampt vectors containing Nampt gene to overexpress Nampt in RBCs and subsequently
examine the NAD+ levels and metabolism in the brain and whole animal over a long-term period. Aim 2 will test
that Nampt OE in RBCs can counteract NAD+ decline and alleviate AD pathologies in APP/PS1 AD mouse model.
Using different methods, we will determine the effect of Nampt OE in RBCs on neuronal degeneration, Amyloid
β (Aβ) burden, adult neurogenesis, cognitive decline, and dementia in AD mouse model. This application is
highly innovative in concept, hypothesis and approach. Targeting RBCs using genetic approach for the therapy
of genetic diseases here AD other than in the blood system may change gene therapy paradigm and represents
a novel therapeutic strategy. Our project is highly feasible based on our preliminary data, thus, has both scientific
and translational significances for AD and other brain diseases.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Shinghua Ding其他文献
Shinghua Ding的其他文献
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{{ truncateString('Shinghua Ding', 18)}}的其他基金
Pathogenesis and motor neuron degeneration of a novel disease associated with a P158A mutation in NAMPT
与 NAMPT P158A 突变相关的新型疾病的发病机制和运动神经元变性
- 批准号:
10563210 - 财政年份:2022
- 资助金额:
$ 39.2万 - 项目类别:
Pathogenesis and motor neuron degeneration of a novel disease associated with a P158A mutation in NAMPT
与 NAMPT P158A 突变相关的新型疾病的发病机制和运动神经元变性
- 批准号:
10444087 - 财政年份:2022
- 资助金额:
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THE ROLE AND MECHANISMS OF PBEF IN ACUTE BRAIN INJURY AND LONG-TERM STROKE OUTCOMES AFTER FOCAL ISCHEMIC STROKE
PBEF 在急性脑损伤和局灶性缺血性卒中后长期卒中结局中的作用和机制
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9535511 - 财政年份:2015
- 资助金额:
$ 39.2万 - 项目类别:
THE ROLE AND MECHANISMS OF PBEF IN ACUTE BRAIN INJURY AND LONG-TERM STROKE OUTCOMES AFTER FOCAL ISCHEMIC STROKE
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9147010 - 财政年份:2015
- 资助金额:
$ 39.2万 - 项目类别:
The Role of Gliotransmission in Cerebral Ischemia
胶质细胞传输在脑缺血中的作用
- 批准号:
8641732 - 财政年份:2010
- 资助金额:
$ 39.2万 - 项目类别:
The Role of Gliotransmission in Cerebral Ischemia
胶质细胞传输在脑缺血中的作用
- 批准号:
8259199 - 财政年份:2010
- 资助金额:
$ 39.2万 - 项目类别:
Reactive astrocytes in neural regeneration and brain recovery after focal ischemic stroke
反应性星形胶质细胞在局灶性缺血性中风后神经再生和大脑恢复中的作用
- 批准号:
10458598 - 财政年份:2010
- 资助金额:
$ 39.2万 - 项目类别:
The Role of Gliotransmission in Cerebral Ischemia
胶质细胞传输在脑缺血中的作用
- 批准号:
8460525 - 财政年份:2010
- 资助金额:
$ 39.2万 - 项目类别:
Reactive astrocytes in neural regeneration and brain recovery after focal ischemic stroke
反应性星形胶质细胞在局灶性缺血性中风后神经再生和大脑恢复中的作用
- 批准号:
10220140 - 财政年份:2010
- 资助金额:
$ 39.2万 - 项目类别:
The Role of Gliotransmission in Cerebral Ischemia
胶质细胞传输在脑缺血中的作用
- 批准号:
8071506 - 财政年份:2010
- 资助金额:
$ 39.2万 - 项目类别:
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