BDNF TrkB- and beta-AR signals in ischemic and non-ischemic cardiomyopathy
BDNF TrkB- and beta-AR signals in ischemic and non-ischemic cardiomyopathy
批准号:
10287657
负责人:
Nazareno Paolocci
金额:
$35.39万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-01-11 至 2022-12-31
关键词:
ADRBK1 geneAccountingAgonistAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAmendmentAmyloid beta-ProteinAnxietyAttenuatedBehavioralBindingBiochemicalBrainBrain DiseasesBrain-Derived Neurotrophic FactorCanis familiarisCardiacChronicCognitiveDepositionDeteriorationDiagnosisDilated CardiomyopathyDiseaseEFRACEvaluationFDA approvedFailureFunctional disorderGenerationsGenesHealthcareHeartHeart DiseasesHeart failureIndividualInfusion proceduresLinkMental DepressionModelingMoodsMusMuscle CellsMyocardialNeurodegenerative DisordersNeuronsOrphanParentsPathogenesisPathogenicityPathologicPathologyPathway interactionsPatientsPerformancePeripheral Nervous SystemPhenotypePhosphotransferasesPlayProtocols documentationPublishingRoleSignal TransductionTestingTherapeuticTropomyosinUnited States National Institutes of HealthUp-RegulationWorkabeta accumulationbasebehavioral studycognitive abilitydruggable targeteffective therapyfootheart functionhyperphosphorylated tauimprovedlong term memorymouse modelneurotrophic factorneurotropicnovelpre-clinicalpreservationpreventprospectivereceptorsmall moleculesphingosine 1-phosphatetau Proteinstherapeutically effective
中文摘要
项目总结
英文摘要
Project Summary
Alzheimer’s disease (AD) and heart failure with preserved ejection fraction (HFpHF) are highly
prevalent diseases. Recent findings show the alarming prospective that they can intertwine in the
same individuals. For both conditions, the therapeutic options remain scant. Following the NIH
initiative directed to penetrate the pathogenesis of either of these diseases to unearth more
effective therapeutic options, here we propose to investigate a new mechanism that AD and
HFpEF may have in common and that can unveil a unifying therapeutic approach for both
diseases. That is: that the concomitant cardiac and central loss in brain-derived neurotrophic
factor (BDNF) and its associated receptor, tropomyosin receptor kinase B (TrkB) accounts for Aβ
pathology and hyperphosphorylated tau deposition and vice-versa, contributing to the onset and
progression of AD and HFpHF. In turn, these two conditions negatively reverberate on each other.
Here, we propose two aims. In the first Aim, using unique gene-edited mouse lines for cardiac
and neuronal BDNF/TrkB signaling, we will determine whether a lack of TrkB/BDNF signaling
fuels Aβ and/or tau pathology, triggering HFpEF and, in turn, the accumulation of Aβ and/or tau
in the heart underlies HFpEF pathogenesis via reduced expression of TrkB/BDNF signaling. In
the second Aim, we will test the impact of specific, agonist-based TrkB stimulation prevents the
accumulation of Aβ and hyperphosphorylated tau in the heart and brain of AD, improving both
cognitive/locomotor and diastolic dysfunction.Of note, in the present proposal, we will put the
evaluation of myocardial performance on equal footing with that of central functions. Indeed, in all
mouse protocols performed here, we will conduct behavioral studies apt to evaluate cognitive
abilities (such as short- and long-term memory) and mood control (anxiety and depression) to
determine whether an improvement of cardiac function via TrkB agonists attenuates behavioral
alterations typically found in patients with AD or HFpEF, or vice versa. The functional parameters
will be also paralleled by the biochemical and pathological assessment, key for the diagnosis of
proteinopathies and for the analysis of the mechanisms.
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DOI:
10.1039/d1sc01550h
发表时间:
2021-05-14
期刊:
Chemical science
影响因子:
8.4
作者:
[Khodade VS, Aggarwal SC, Pharoah BM, Paolocci N, Toscano JP]
通讯作者:
Toscano JP
DOI:
10.3390/antiox11020382
发表时间:
2022-02-14
期刊:
Antioxidants (Basel, Switzerland)
影响因子:
--
作者:
[Mancardi D, Pagliaro P, Ridnour LA, Tocchetti CG, Miranda K, Juhaszova M, Sollott SJ, Wink DA, Paolocci N]
通讯作者:
Paolocci N
Metabolic remodelling of glucose, fatty acid and redox pathways in the heart of type 2 diabetic mice.
2 型糖尿病小鼠心脏中葡萄糖、脂肪酸和氧化还原途径的代谢重塑。
DOI:
10.1113/jp276824
发表时间:
2020-04
期刊:
The Journal of physiology
影响因子:
--
作者:
[Cortassa S, Caceres V, Tocchetti CG, Bernier M, de Cabo R, Paolocci N, Sollott SJ, Aon MA]
通讯作者:
Aon MA
DOI:
10.7554/elife.80949
发表时间:
2022-12-14
期刊:
eLife
影响因子:
7.7
作者:
[Tarasov KV, Chakir K, Riordon DR, Lyashkov AE, Ahmet I, Perino MG, Silvester AJ, Zhang J, Wang M, Lukyanenko YO, Qu JH, Barrera MC, Juhaszova M, Tarasova YS, Ziman B, Telljohann R, Kumar V, Ranek M, Lammons J, Bychkov R, de Cabo R, Jun S, Keceli G, Gupta A, Yang D, Aon MA, Adamo L, Morrell CH, Otu W, Carroll C, Chambers S, Paolocci N, Huynh T, Pacak K, Weiss R, Field L, Sollott SJ, Lakatta EG]
通讯作者:
Lakatta EG
DOI:
10.1161/circresaha.121.319648
发表时间:
2022-03-04
期刊:
Circulation research
影响因子:
20.1
作者:
[Keceli G, Gupta A, Sourdon J, Gabr R, Schär M, Dey S, Tocchetti CG, Stuber A, Agrimi J, Zhang Y, Leppo M, Steenbergen C, Lai S, Yanek LR, O'Rourke B, Gerstenblith G, Bottomley PA, Wang Y, Paolocci N, Weiss RG]
通讯作者:
Weiss RG
共 13 条
BDNF TrkB- and beta-AR signals in ischemic and non-ischemic cardiomyopathy
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批准号:9447993
-
项目类别:
-
资助金额:$59.24万
-
财政年份:2018
-
负责人:Nazareno Paolocci
-
依托单位:
Nitroxyl cardiac effects are mediated by cAMP/PKA signal
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批准号:7433770
-
项目类别:
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资助金额:$37.59万
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财政年份:2005
-
负责人:Nazareno Paolocci
-
依托单位:
Nitroxyl cardiac effects are mediated by cAMP/PKA signal
-
批准号:7101684
-
项目类别:
-
资助金额:$37.8万
-
财政年份:2005
-
负责人:Nazareno Paolocci
-
依托单位:
Nitroxyl cardiac effects are mediated by cAMP/PKA signal
-
批准号:7255482
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项目类别:
-
资助金额:$37.61万
-
财政年份:2005
-
负责人:Nazareno Paolocci
-
依托单位:
Nitroxyl cardiac effects are mediated by cAMP/PKA signal
-
批准号:6926499
-
项目类别:
-
资助金额:$39.43万
-
财政年份:2005
-
负责人:Nazareno Paolocci
-
依托单位:
海外基金