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
脊髓和球性肌萎缩症(SBMA)是一种以丧失为特征的神经肌肉疾病
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