Identification of the Neuroprotective STX Receptor in the Brain
大脑中神经保护性 STX 受体的鉴定
基本信息
- 批准号:10571667
- 负责人:
- 金额:$ 23.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-12-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AcademyAccelerationAlkynesAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease patientAmericanAmyloidAmyloid beta-ProteinAzidesBiologicalBrainBreast Cancer Risk FactorCRISPR/Cas technologyCalcium SignalingCellsCentral Nervous SystemChemistryClinicalClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsConjugated EstrogensCore FacilityCoupledDataDementiaDevelopmentDiazomethaneElectrophysiology (science)EndocrinologistEstradiolEstrogen Nuclear ReceptorEstrogen ReceptorsEstrogensEventExhibitsGene DeletionGoalsGuide RNAHippocampusHormone replacement therapyHypothalamic structureIn VitroIsomerismLabelLigandsMeasuresMembraneMitochondriaMolecularMusMutagenesisNeurologyNeuronsOralOral AdministrationPhysiologicalPostmenopausePro-OpiomelanocortinProcessProteinsProteomicsReceptor ActivationRecommendationResearchReverse Transcriptase Polymerase Chain ReactionRodentSelective Estrogen Receptor ModulatorsSenile PlaquesShiga ToxinSignal PathwaySignal TransductionSliceSmall Interfering RNAStaphylococcus aureusStructure of nucleus infundibularis hypothalamiSynaptic TransmissionTherapeuticToxic effectUnited StatesVirusWomanadeno-associated viral vectorblood-brain barrier crossingcandidate identificationcrosslinkdesigneffective therapyestrogenicexperimental studyfluorophoreimprovedin vivoknock-downmRNA Expressionmouse modelneuron lossneuroprotectionnonhuman primatenovelnovel therapeuticspharmacologicpreventreceptorrecombinaseresponseside effectthrombotic
项目摘要
PROJECT SUMMARY
Currently, there are over 5.7 million Alzheimer’s disease (AD) patients in the United States, and this number is
predicted to reach over 14 million by the year 2050. Despite decades of research, effective therapies for treating
AD remain lacking, and recent clinical trials targeting β-amyloid plaques (Aβ) have been largely unsuccessful.
Nearly two-thirds of AD patients are postmenopausal women who have lost the neuropr otective effects of
estrogens. Studies on hormone replacement therapy raised hopes that 17β-estradiol (E2) might provide an
effective treatment for preventing neuronal loss, but a large clinical trial found that conjugated estrogens caused
an increased risk of breast cancer and thrombotic events. As an alternative, we have synthesized and
characterized a non-steroidal estrogenic ligand, STX that selectively targets an unidentified receptor in the
central nervous system (CNS), but importantly STX does not engage the “classical” nuclear estrogen receptors,
which enables STX to avoid the unfavorable effects of estrogen. Orally administered STX crosses the blood
brain barrier and activates neuroprotective signaling pathways in CNS neurons. STX improves mitochondrial
function and enhances neuronal synaptic transmission. Moreover, STX protects against amyloid toxicity in
cultured hippocampal neurons, while sustained oral STX protects against amyloid toxicity in a mouse model of
AD. Therefore, STX has a high therapeutic potential, but identification of the receptor is needed for further
development as a treatment for AD. Based on physiological / pharmacological data, we hypothesize that STX
targets a Gq-coupled membrane estrogen receptor in CNS neurons to provide neuroprotective actions. We
propose to isolate this receptor using photo-crosslinking and click chemistries and confirm its identity via in vivo
CRISPR/Cas9 mutagenesis studies. We have designed and synthesized a novel bifunctional STX derivative
(BF-STX) that contains a photo-crosslinkablediazirine group and an alkyne group, which permits specific tagging
of STX-protein conjugates with a fluorophore and the isolation of STX-protein conjugates from cell lysates for
proteomic analysis. Photo-crosslinked BF-STX labels POMC-expressing hypothalamic (mHypo43) cells in vitro.
Therefore, we will: (1) photo-crosslink BF-STX to candidate receptors in mHypo43 cell lysates and isolate BF-
STX-protein conjugates from the membrane fraction via click chemistry to azide-bearing beads and analyze by
proteomics. The most promising hits will be validated by siRNA knock-down in mHypo43 cells followed by
measuring the loss of STX signaling; and (2) validate promising receptor candidates in vivo using CRISPR/Cas9
mutagenesis in POMCCre mice. Single adeno-associated viral (AAV) vectors containing recombinase-dependent
Staphylococcus aureus Cas9 and a single guide RNA against each candidate receptor will be targeted to POMC
neurons. Molecular biological (single cell RT-PCR) and electrophysiological experiments will be conducted to
validate the reduction in mRNA expression and loss of physiological responses to STX. The results from these
studies will help to develop STX as a novel therapeutic for treating postmenopausal women and AD.
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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Martin Jeffrey Kelly其他文献
Martin Jeffrey Kelly的其他文献
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{{ truncateString('Martin Jeffrey Kelly', 18)}}的其他基金
Cross-talk between Leptin and Estrogen Signaling in Hypothalamic Arcuate Neurons
下丘脑弓状神经元中瘦素和雌激素信号传导之间的串扰
- 批准号:
7993025 - 财政年份:2005
- 资助金额:
$ 23.1万 - 项目类别:
Cross-Talk Between Estrogen and Metabolic Hormone Signaling in Arcuate Neurons
弓状神经元中雌激素和代谢激素信号传导之间的串扰
- 批准号:
9174776 - 财政年份:2005
- 资助金额:
$ 23.1万 - 项目类别:
Cross-Talk between Leptin and Estrogen Signaling in Hypothalamic Arcuate Neurons
下丘脑弓状神经元中瘦素和雌激素信号传导之间的串扰
- 批准号:
8307979 - 财政年份:2005
- 资助金额:
$ 23.1万 - 项目类别:
Crosstalk between Estrogen and Metabolic Hormone Signaling in Kisspeptin Neurons
Kisspeptin 神经元中雌激素和代谢激素信号传导之间的串扰
- 批准号:
10246663 - 财政年份:2005
- 资助金额:
$ 23.1万 - 项目类别:
Cross-talk between Estrogen and Metabolic Hormone Signaling in Kisspeptin Neurons
Kisspeptin 神经元中雌激素和代谢激素信号传导之间的串扰
- 批准号:
10295726 - 财政年份:2005
- 资助金额:
$ 23.1万 - 项目类别:
Cross-talk between Estrogen and Metabolic Hormone Signaling in Kisspeptin Neurons
Kisspeptin 神经元中雌激素和代谢激素信号传导之间的串扰
- 批准号:
10473890 - 财政年份:2005
- 资助金额:
$ 23.1万 - 项目类别:
Cross-talk between Leptin and Estrogen Signaling in Hypothalamic Arcuate Neurons
下丘脑弓状神经元中瘦素和雌激素信号传导之间的串扰
- 批准号:
8113859 - 财政年份:2005
- 资助金额:
$ 23.1万 - 项目类别:
Cross-Talk between Leptin and Estrogen Signaling in Hypothalamic Arcuate Neurons
下丘脑弓状神经元中瘦素和雌激素信号传导之间的串扰
- 批准号:
8488293 - 财政年份:2005
- 资助金额:
$ 23.1万 - 项目类别:
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