Repurposing FDA-approved agonists of HCAR2 as novel therapeutics for Alzheimer's Disease
将 FDA 批准的 HCAR2 激动剂重新用作阿尔茨海默病的新型疗法
基本信息
- 批准号:10416432
- 负责人:
- 金额:$ 169.15万
- 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:2022-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AffinityAge-MonthsAge-associated memory impairmentAgonistAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease patientAlzheimer&aposs disease therapeuticAlzheimer&aposs disease therapyAnimal ModelBehavioralBlood - brain barrier anatomyBrainClinicalClinical TrialsCognitiveDataDemyelinationsDiseaseDissectionDyslipidemiasEnzymesFDA approvedFormulationFumaratesG-Protein-Coupled ReceptorsGenesGeneticGenetic ModelsHumanImpaired cognitionInfarctionIntakeKnock-outLesionLigandsMediatingMetabolicMethodologyMicrogliaModelingMultiple SclerosisMusNerve DegenerationNeurodegenerative DisordersNeuroimmunomodulationNeuronal InjuryNeuronsNeutrophil InfiltrationNicotinic AcidsOralOutcomeParkinson DiseasePathologyPathway interactionsPatientsPeripheralPhagocytesPharmaceutical PreparationsPharmacologyPhenotypeReporterReportingRiskRodentRoleStrokeTherapeuticTherapeutic EffectTherapeutic StudiesTimeTissuesTreatment EfficacyValidationappropriate dosecognitive functioncognitive performancedietarydrug efficacyeffective therapyfrailtyhuman pluripotent stem cellimprovedin vivomouse modelneuron lossnew therapeutic targetnicotinatenovelnovel therapeuticspharmacokinetics and pharmacodynamicspre-clinicalreceptorresponsestroke modeltherapeutic effectivenesstherapeutic targettherapeutically effectivetranscriptometranscriptome sequencingtranscriptomicstreatment strategy
项目摘要
Alzheimer’s disease (AD) is a devastating neurodegenerative disease for which there are no effective
treatments. Low dietary niacin intake increases the risk of cognitive frailty and niacin deficiency leads to
neurodegeneration. Conversely, higher niacin intake is associated with improved cognitive performance,
reduced risk of cognitive decline and AD. Niacin actions in the brain are distinct from other tissues where it is not
used as a metabolic substrate, but exerts its actions principally through its ability to activate HCAR2 (GPR109A),
a GPCR that is expressed in the brain selectively by microglia.
Niaspan® is the FDA approved formulation of niacin and is used clinically to treat dyslipidemia. Recenty, it has
been appreciated that monomethyl fumarate (MMF), the bioactive metabolite of dimethyl fumarate (DMF) is an
agonist of HCAR2. Tecfidera® is the FDA-approved formulation of DMF used clinically to treat multiple sclerosis
(MS). HCAR2 activation with niacin or DMF elicits neuroprotective effects in Parkinson's disease, stroke, and
MS models. Niacin treatment of Parkinson’s patients improved clinical outcomes and there is an ongoing clinical
trial (NCT03808961). Niacin treatment of a murine model of MS, induces a protective microglial phenotype. The
effect of these agonists has not been investigated in AD or its animal models. We hypothesize that agonists of
HCAR2 are of therapeutic utility in AD.
We provide preliminary evidence there is a robust induction of HCAR2 expression by microglia in the AD brain.
Genetic inactivation of Hcar2 increases plaque burden and accelerates cognitive impairment in 5xFAD AD
mouse model. Conversely, Niaspan® treatment reduced plaque burden and neuronal pathology, suggesting that
pharmacological activation of HCAR2 is a viable therapeutic strategy for AD.
We will study the repuporsing potential of the FDA-approved agonists of HCAR2, Niaspan® and Tecfidera®
for AD in the preclinical level using the 5xFAD mouse model of AD.
Aim 1) Evaluate the therapeutic efficacy and pharmacological target of the FDA-approved drugs
Niaspan® and Tecfidera® in the 5xFAD amyloidogenic mouse model We propose to establish an optimal
effective therapeutic strategy for treatment of 5xFAD mice. We will treat mice with HCAR2 agonists at early and
late disease stages and for diferent periods of time. Drug efficacy will be evaluated by a battery of phenotypic
and behavioral readouts. Pharmacokinetic and pharmacodynamic studies will be performed. We will establish
whether the effects HCAR2 agonists arise exclusively from microglial HCAR2 by its selective and inducible
inactivation using Cx3cr1CreERT2;Hcar2fl/fl;5xFAD mice.
Aim 2) Analyze microglial transcriptomic profiles induced by Niaspan® and Tecfidera® in AD
We will determine the effect of Niaspan® and Tecfidera® on the microglial transcriptome by RNA-seq analysis
of cultured microglia activated with Aβ1-42 aggregates and treated with these drugs. Both primary murine microglia
and human pluripotent stem cells (hPSC)-derived microglia will be analyzed to establish if the actions of
Niaspan® and Tecfidera® are comparable between human and murine microglia. We will carry out a parallel in
vivo analysis of microglial subpopulations expressing high and low levels of Hcar2 isolated from 5xFAD mice
treated with Niaspan® and Tecfidera® using an mRFP-reporter line. These studies will identify target genes and
pathways modulated by HCAR2 activation in microglia which subserve its neuroprotective effects in AD, and
allow the dissection of underlying mechanisms.
阿尔茨海默病(Alzheimer's disease,AD)是一种严重的神经退行性疾病,目前尚无有效的治疗方法。
治疗。饮食中烟酸摄入量低会增加认知功能脆弱的风险,烟酸缺乏会导致
神经变性相反,较高的烟酸摄入量与认知能力的改善有关,
降低认知能力下降和AD的风险。烟酸在大脑中的作用与其他组织不同,
用作代谢底物,但主要通过其激活HCAR 2(GPR 109 A)的能力发挥其作用,
一种由小胶质细胞选择性地在脑中表达的GPCR。
Niaspan®是FDA批准的烟酸制剂,临床上用于治疗血脂异常。最近,
已经认识到,富马酸单甲酯(MMF),富马酸二甲酯(DMF)的生物活性代谢物,是一种
HCAR 2的激动剂。Tecfidera®是FDA批准的DMF制剂,临床上用于治疗多发性硬化症
(MS)中定义。烟酸或DMF激活HCAR 2可增强帕金森病、中风和脑梗死患者的神经保护作用。
MS模型。烟酸治疗帕金森病患者改善了临床结局,目前正在进行临床研究。
试验(NCT 03808961)。烟酸治疗MS小鼠模型诱导保护性小胶质细胞表型。的
尚未在AD或其动物模型中研究这些激动剂的作用。我们假设,
HCAR 2在AD中具有治疗效用。
我们提供了初步证据,有一个强大的诱导HCAR 2表达的小胶质细胞在AD脑。
Hcar 2基因失活增加了5xFAD AD患者的斑块负担并加速了认知障碍
小鼠模型相反,Niaspan®治疗减少了斑块负荷和神经元病理学,表明
HCAR 2的药理学活化是AD的可行治疗策略。
我们将研究FDA批准的HCAR 2激动剂、Niaspan®和Tecfidera®的抗肿瘤潜力。
使用AD的5xFAD小鼠模型,在临床前水平对AD进行评估。
目的1)评价FDA批准药物的疗效和药理作用靶点
Niaspan®和Tecfidera®在5xFAD淀粉样蛋白生成小鼠模型中的应用
用于治疗5xFAD小鼠的有效治疗策略。我们将在早期用HCAR 2激动剂治疗小鼠,
晚期疾病阶段和不同时期。药物疗效将通过一组表型
和行为读数。将进行药代动力学和药效学研究。我们将建立
HCAR 2激动剂的作用是否仅由小胶质细胞HCAR 2通过其选择性和诱导性而产生
使用Cx 3cr 1CreERT 2; Hcar 2fl/fl;5xFAD小鼠进行灭活。
目的2)分析AD中Niaspan®和Tecfidera®诱导的小胶质细胞转录组学谱
我们将通过RNA-seq分析确定Niaspan®和Tecfidera®对小胶质细胞转录组的影响
用Aβ1-42聚集体激活的培养小胶质细胞,并用这些药物处理。原代小鼠小胶质细胞
和人多能干细胞(hPSC)衍生的小胶质细胞的作用,以确定
Niaspan®和Tecfidera®在人和鼠小胶质细胞之间是相当的。我们将进行一个平行的,
从5xFAD小鼠分离的表达高水平和低水平Hcar 2的小胶质细胞亚群的体内分析
用Niaspan®和Tecfidera®处理,使用mRFP-报告细胞系。这些研究将确定靶基因,
在小胶质细胞中通过HCAR 2活化调节的途径,其在AD中发挥神经保护作用,
允许解剖潜在的机制。
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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GARY E. LANDRETH其他文献
GARY E. LANDRETH的其他文献
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{{ truncateString('GARY E. LANDRETH', 18)}}的其他基金
Training Grant on Alzheimer's Disease and ADRD at Indiana University
印第安纳大学阿尔茨海默病和 ADRD 培训补助金
- 批准号:
10627778 - 财政年份:2021
- 资助金额:
$ 169.15万 - 项目类别:
Training Grant on Alzheimer's Disease and ADRD at Indiana University
印第安纳大学阿尔茨海默病和 ADRD 培训补助金
- 批准号:
10161389 - 财政年份:2021
- 资助金额:
$ 169.15万 - 项目类别:
Training Grant on Alzheimer's Disease and ADRD at Indiana University
印第安纳大学阿尔茨海默病和 ADRD 培训补助金
- 批准号:
10393637 - 财政年份:2021
- 资助金额:
$ 169.15万 - 项目类别:
Microglial hexokinase 2 as a therapeutic target in Alzheimer's disease
小胶质细胞己糖激酶 2 作为阿尔茨海默病的治疗靶点
- 批准号:
10033043 - 财政年份:2020
- 资助金额:
$ 169.15万 - 项目类别:
Academic Leadership Award at the Indiana University School of Medicine
印第安纳大学医学院学术领导奖
- 批准号:
10359680 - 财政年份:2020
- 资助金额:
$ 169.15万 - 项目类别:
Academic Leadership Award at the Indiana University School of Medicine
印第安纳大学医学院学术领导奖
- 批准号:
10532250 - 财政年份:2020
- 资助金额:
$ 169.15万 - 项目类别:
Academic Leadership Award at the Indiana University School of Medicine
印第安纳大学医学院学术领导奖
- 批准号:
9892249 - 财政年份:2020
- 资助金额:
$ 169.15万 - 项目类别:
Academic Leadership Award at the Indiana University School of Medicine
印第安纳大学医学院学术领导奖
- 批准号:
10077811 - 财政年份:2020
- 资助金额:
$ 169.15万 - 项目类别:
Actions of Nuclear Receptors on TREM2+ myeloid cells and microglia in AD brain
核受体对 AD 脑中 TREM2 髓系细胞和小胶质细胞的作用
- 批准号:
9104448 - 财政年份:2016
- 资助金额:
$ 169.15万 - 项目类别:
Actions of Nuclear Receptors on TREM2+ myeloid cells and microglia in AD brain
核受体对 AD 脑中 TREM2 髓系细胞和小胶质细胞的作用
- 批准号:
9416662 - 财政年份:2016
- 资助金额:
$ 169.15万 - 项目类别: