Cell-Cell Interactions In Alzheimer's disease and related dementias
Cell-Cell Interactions In Alzheimer's disease and related dementias
批准号:
10711899
负责人:
Madhuri Kango-Singh
金额:
$31.48万
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
项目状态:
未结题
起止时间:
2021-08-01 至 2026-06-30
关键词:
AffectAlzheimer disease detectionAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease patientAlzheimer&aposs disease related dementiaAmyloid beta-42Amyloid beta-ProteinAtrophicBiological MarkersBrainBrain regionCartoonsCaspaseCell CommunicationCell DeathCell Differentiation processCell ProliferationCell SurvivalCellsCerebral cortexComplexDataDevelopmentDiseaseDisease ProgressionDrosophila eyeDrosophila genusDrosophila melanogasterEtiologyEventExhibitsEyeGene ExpressionGene ProteinsGenesGeneticGoalsGrowthHippocampusHumanImpaired cognitionInterventionLearningMeasuresMediatingMemoryMitotic RecombinationModelingMolecularMolecular GeneticsN-terminalNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNeuronsPathologyPathway interactionsPatientsPeptidesPhasePhosphotransferasesPopulationProteinsReporterRoleSamplingSignal PathwaySignal TransductionStudy modelsSystemTestingTherapeuticTimeTransgenic OrganismsTranslatingWNT Signaling PathwayWestern Blottingabeta accumulationantagonistcell typecognitive functionearly detection biomarkersexperimental studyflygain of functiongenetic makeupgenome-widehuman diseasehuman modelloss of functionmembermodel organismmorphogensmosaicneuron lossneuropathologyneurotoxicneurotoxicitynew therapeutic targetpolypeptidepreventprogressive neurodegenerationresponseretinal neuronsensortau Proteinstherapeutic targettooltranscriptome sequencingtransgenic model of alzheimer disease
中文摘要
阿尔茨海默病(以下简称AD)是一种进行性神经退行性疾病,是致命的,没有有效的治疗方法
英文摘要
Alzheimer’s disease (hereafter, AD), a progressive neurodegenerative disorder, is fatal with no effective
cure to date. AD manifests as gradual decline in cognitive functions of learning and memory due to
selective atrophy of the hippocampus and frontal cerebral cortex in the brain. The neurodegeneration
associated with AD also coincides with accumulation of amyloid-beta 42 (Aß42) plaques. The accumulation
of Aβ42 plaques and NFTs in AD triggers progressive neurodegeneration across brain regions. It is not
clear how cellular changes contribute to the progression from an initial asymptomatic period into a phase
of stark cognitive decline. The molecular genetic mechanisms underlying the Aβ42 mediated
neurodegeneration are not fully understood. Many strategies including model organisms have been
devised. Drosophila melanogaster, fruit fly, with a large array of genetic tools, and similar genetic makeup
to humans is an excellent model for human diseases including AD. Drosophila can be used for high
throughput genome wide- and for therapeutic compound screens. We have established a transgenic fly
model where we misexpress high levels of human Aß42 polypeptides in the retinal neurons of the eye,
which exhibits AD like neuropathology of progressive neuronal death. This stable transgenic line exhibits
Aß42 mediated cell death in nearly 100% flies at 29oC. Our goal is to employ our Drosophila eye model to
identify (a) downstream target genes and (b) reporters/ sensors to detect AD, and (c) look for complex
interaction between Aß42-producing and wild-type neurons during Alzheimer’s neuropathology. We
identified the highly conserved growth regulatory Wingless (Wg)/Wnt signaling pathway as the dominant
modifier of Aß42-mediated neurodegeneration. The first aim is to determine the involvement of Wg
signaling in Aβ42-mediated neurodegeneration. Wg signaling has been studied in cell survival and
differentiation, and not in neurodegeneration. We will test if modulation of the Wg signaling pathway can
modulate Aβ42-mediated neurodegeneration. We will test if the reporters/sensors of the Wg pathway can
be used to detect Aß42-mediated neurodegeneration. In the second aim, we will determine if Wg pathway
activation triggers neurodegeneration in wild-type cells or in Aβ42-expressing cells. We will use our two
clone systems to determine if there is any cross-talk between the wild-type neurons and Aß42 producing
neurons. Our hypothesis is that aberrant Wg signaling might trigger cell death in wild-type neurons. These
proposed studies aim to provide a useful blueprint to study cross-talk between cell populations in
neurodegenerative disease. This may potentially identify new biomarkers that can be differentially
regulated between Aβ42-expressing and WT neurons. Better understanding of the local context of cell
death in progressive neurodegenerative disease is a vital next step in developing new interventions to slow
or halt disease progression.
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DOI:
10.1016/j.ydbio.2011.08.017
发表时间:
2011-11-15
期刊:
Developmental biology
影响因子:
2.7
作者:
[Singh A, Tare M, Kango-Singh M, Son WS, Cho KO, Choi KW]
通讯作者:
Choi KW
DOI:
10.1038/s41419-023-05973-z
发表时间:
2023-07-28
期刊:
CELL DEATH & DISEASE
影响因子:
9
作者:
[Deshpande, Prajakta, Chimata, Anuradha Venkatakrishnan, Snider, Emily, Singh, Aditi, Kango-Singh, Madhuri, Singh, Amit]
通讯作者:
Singh, Amit
DOI:
10.1038/s41419-023-06361-3
发表时间:
2024-01-18
期刊:
CELL DEATH & DISEASE
影响因子:
9
作者:
[Deshpande, Prajakta, Chen, Chao-Yi, Chimata, Anuradha Venkatakrishnan, Li, Jian-Chiuan, Sarkar, Ankita, Yeates, Catherine, Chen, Chun-Hong, Kango-Singh, Madhuri, Singh, Amit]
通讯作者:
Singh, Amit
DOI:
10.2144/btn-2021-0006
发表时间:
2021-08
期刊:
BioTechniques
影响因子:
2.7
作者:
[]
通讯作者:
DOI:
10.4103/1673-5374.354516
发表时间:
2023-04
期刊:
Neural regeneration research
影响因子:
6.1
作者:
[Yeates C, Deshpande P, Kango-Singh M, Singh A]
通讯作者:
Singh A
共 9 条
Genetic Basis of Dorso-Ventral Patterning in the Drosophila Eye
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批准号:10652488
-
项目类别:
-
资助金额:$32.85万
-
财政年份:2021
-
负责人:Madhuri Kango-Singh
-
依托单位:
Genetic Basis of Dorso-Ventral Patterning in the Drosophila Eye
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批准号:10279832
-
项目类别:
-
资助金额:$32.85万
-
财政年份:2021
-
负责人:Madhuri Kango-Singh
-
依托单位:
Genetic Basis of Dorso-Ventral Patterning in the Drosophila Eye
-
批准号:10459551
-
项目类别:
-
资助金额:$31.87万
-
财政年份:2021
-
负责人:Madhuri Kango-Singh
-
依托单位: