Targeting epigenetic modifiers of androgen receptor activity and toxicity in SBMA
Targeting epigenetic modifiers of androgen receptor activity and toxicity in SBMA
批准号:
9754495
负责人:
Udai B Pandey
金额:
$39.73万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-04-01 至 2022-03-31
关键词:
ATAC-seqAffectAmino AcidsAndrogen ReceptorAndrogensAnimal ModelArginineBindingBiologyBiopsy SpecimenCell Differentiation processCellsCessation of lifeChIP-seqConsensusCultured CellsCytosolDNA BindingDiseaseEpigenetic ProcessFutureGene ExpressionGenesGeneticGenetic TranscriptionGlutamineGoalsHormonesInterventionKennedy SyndromeKnock-inKnock-in MouseLengthLysineMediatingMethylationModelingModificationMolecularMotor NeuronsMusMuscleMuscle FibersNerve DegenerationNeuromuscular DiseasesNuclear TranslocationPathogenesisPathologyPathway interactionsPatientsPeripheralPharmacologyPhosphorylationPost-Translational Protein ProcessingPreparationProcessProtein MethylationProtein-Arginine N-MethyltransferaseReceptor GeneRegulationResearchSerineSerumSiteSkeletal MuscleStanoloneTestingTestosteroneTissuesToxic effectTransactivationTransgenic OrganismsValidationandrogen sensitivebaseflygain of functionknock-downmalemouse modelneuromuscularneurotoxicitynew therapeutic targetnovelnovel therapeutic interventionpolyglutaminepromoterprostate cancer cellreceptor functionrecruitskeletal muscle wastingspinal and bulbar muscular atrophytranscriptome sequencing
中文摘要
脊髓延髓肌萎缩症(SBMA)是一种神经肌肉疾病的特点是损失
下运动神经元和骨骼肌萎缩。SBMA由CAG扩增(>38
重复),其在雄激素受体(AR)基因中编码多聚谷氨酰胺(polyQ)区。的
这种疾病完全表现在男性身上,因为他们的血清中有高水平的雄激素。PolyQ-AR
在与雄激素、睾酮和双氢睾酮结合后转化为有毒物质
(DHT)。
我们建议鉴定参与调节polyQ-AR介导的毒性的基因,
推进我们对SBMA发病机制的分子机制的理解。
目前R21应用的主要目的是确定转录共调节子
AR介导polyQ-AR的毒性功能获得性(GOF)。我们假设两个AR
转录辅助调节因子,即蛋白质精氨酸甲基转移酶6(PRMT 6)和赖氨酸
脱甲基酶1(LSD 1)协同合作,通过以下方式增强polyQ-AR的毒性GOF:
改变其转录活性。我们的假设是基于我们的观察,后-
AR的翻译修饰(磷酸化和甲基化)是重要的决定因素
的毒性。我们将利用SBMA的良好表征的小鼠模型(转基因AR 100 Q
和敲入AR 113 Q小鼠),其显示激素和谷氨酰胺长度依赖性
神经肌肉无力、肌肉病理和过早死亡。SBMA转基因和敲入
小鼠是研究疾病发病机制和测试药理学的良好模型。
干预我们建议确定多聚Q-AR的协同调节因子如何在SBMA中发挥作用。我们
期望确定AR功能如何在骨骼肌中调节和在SBMA中失调。
英文摘要
Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder characterized by loss
of lower motor neurons and skeletal muscle atrophy. SBMA is caused by CAG expansions (>38
repeats) encoding a polyglutamine (polyQ) tract in the androgen receptor (AR) gene. The
disease fully manifests in males, as they have high levels of androgens in the serum. PolyQ-AR
is converted to a toxic species upon binding to androgens, testosterone and dihydrotestosterone
(DHT).
We propose to identify the genes involved in regulating polyQ-AR-mediated toxicity and
advance our understanding about the molecular mechanisms underlying SBMA pathogenesis.
The main objective of current R21 application is to determine that transcriptional co-regulators
of AR mediate the toxic gain-of-function (GOF) of polyQ-AR. We hypothesize that two AR
transcription co-regulators, namely protein arginine methyltransferase 6 (PRMT6) and lysine
demethylase 1 (LSD1), synergistically cooperate to enhance the toxic GOF of polyQ-AR by
changing its transcriptional activity. Our hypothesis is based on our observations that post-
translational modifications (phosphorylation and methylation)) of AR are important determinant
of the toxicity. We will utilize well-characterized mouse models of SBMA (transgenic AR100Q
and knock-in AR113Q mice) that show hormone- and glutamine length–dependent
neuromuscular weakness, muscle pathology, and early death. SBMA transgenic and knock-in
mice represent good models to study disease pathogenesis and to test pharmacologic
intervention. We propose to determine how co-regulators of polyQ-AR function in SBMA. We
expect to determine how AR function is regulated in skeletal muscle and dysregulated in SBMA.
期刊论文(4)
专著(0)
科研奖励(0)
会议论文
DOI:
10.3390/cells11132105
发表时间:
2022-07-03
期刊:
CELLS
影响因子:
6
作者:
[Marchioretti, Caterina, Zuccaro, Emanuela, Pandey, Udai Bhan, Rosati, Jessica, Basso, Manuela, Pennuto, Maria]
通讯作者:
Pennuto, Maria
Clenbuterol-sensitive delayed outward potassium currents in a cell model of spinal and bulbar muscular atrophy.
脊髓和延髓肌萎缩细胞模型中克伦特罗敏感的延迟外向钾电流。
DOI:
10.1007/s00424-021-02559-6
发表时间:
2021
期刊:
Pflugers Archiv : European journal of physiology
影响因子:
--
作者:
[Martínez-Rojas,VladimirA, Arosio,Daniele, Pennuto,Maria, Musio,Carlo]
通讯作者:
Musio,Carlo
Identifying the molecular mechanisms of GEMIN5 mutations in a novel cerebellar ataxia syndrome
-
批准号:10753403
-
项目类别:
-
资助金额:$53.97万
-
财政年份:2023
-
负责人:Udai B Pandey
-
依托单位:
Cellular and Molecular Mechanisms of FUS-related Amyotrophic Lateral Sclerosis
-
批准号:9303039
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2017
-
负责人:Udai B Pandey
-
依托单位:
Cellular and Molecular Mechanisms of FUS-related Amyotrophic Lateral Sclerosis
-
批准号:9230443
-
项目类别:
-
资助金额:$32.92万
-
财政年份:2014
-
负责人:Udai B Pandey
-
依托单位:
Cellular and Molecular Mechanisms of FUS-related Amyotrophic Lateral Sclerosis
-
批准号:9014564
-
项目类别:
-
资助金额:$32.94万
-
财政年份:2014
-
负责人:Udai B Pandey
-
依托单位:
Cellular and Molecular Mechanisms of FUS-related Amyotrophic Lateral Sclerosis
-
批准号:8811504
-
项目类别:
-
资助金额:$34.05万
-
财政年份:2014
-
负责人:Udai B Pandey
-
依托单位:
Cellular and Molecular Mechanisms of FUS-related ALS/FTD
-
批准号:10370356
-
项目类别:
-
资助金额:$38.75万
-
财政年份:2013
-
负责人:Udai B Pandey
-
依托单位:
Cellular and Molecular Mechanisms of FUS-related ALS/FTD
-
批准号:9901635
-
项目类别:
-
资助金额:$38.39万
-
财政年份:2013
-
负责人:Udai B Pandey
-
依托单位:
Cellular and Molecular Mechanisms of FUS-related ALS/FTD
-
批准号:9763021
-
项目类别:
-
资助金额:$38.41万
-
财政年份:2013
-
负责人:Udai B Pandey
-
依托单位:
Cellular and Molecular Mechanisms of FUS-related Amyotrophic Lateral Sclerosis
-
批准号:8529133
-
项目类别:
-
资助金额:$32.49万
-
财政年份:2013
-
负责人:Udai B Pandey
-
依托单位:
Cellular and Molecular Mechanisms of FUS-related ALS/FTD
-
批准号:10582582
-
项目类别:
-
资助金额:$38.83万
-
财政年份:2013
-
负责人:Udai B Pandey
-
依托单位:
海外基金