Targeting epigenetic modifiers of androgen receptor activity and toxicity in SBMA

SBMA 中雄激素受体活性和毒性的表观遗传修饰因子

基本信息

批准号：
9754495
负责人：
Udai B Pandey
金额：
$ 39.73万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754495
关键词：
ATAC-seq Affect Amino Acids Androgen Receptor Androgens Animal Model Arginine Binding Biology Biopsy Specimen Cell Differentiation process Cells Cessation of life ChIP-seq Consensus Cultured Cells Cytosol DNA Binding Disease Epigenetic Process Future Gene Expression Genes Genetic Genetic Transcription Glutamine Goals Hormones Intervention Kennedy Syndrome Knock-in Knock-in Mouse Length Lysine Mediating Methylation Modeling Modification Molecular Motor Neurons Mus Muscle Muscle Fibers Nerve Degeneration Neuromuscular Diseases Nuclear Translocation Pathogenesis Pathology Pathway interactions Patients Peripheral Pharmacology Phosphorylation Post-Translational Protein Processing Preparation Process Protein Methylation Protein-Arginine N-Methyltransferase Receptor Gene Regulation Research Serine Serum Site Skeletal Muscle Stanolone Testing Testosterone Tissues Toxic effect Transactivation Transgenic Organisms Validation androgen sensitive base fly gain of function knock-down male mouse model neuromuscular neurotoxicity new therapeutic target novel novel therapeutic intervention polyglutamine promoter prostate cancer cell receptor function recruit skeletal muscle wasting spinal and bulbar muscular atrophy transcriptome sequencing

项目摘要

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.

脊柱和鳞茎肌肉萎缩（SBMA）是一种神经肌肉疾病，其特征是丧失低运动神经元和骨骼肌萎缩的。 SBMA是由CAG扩展引起的（> 38 重复序列）编码雄激素受体（AR）基因中的聚谷氨酰胺（polyq）。疾病在雄性中完全表现出来，因为它们在血清中具有高水平的雄激素。 polyq-ar 在与雄激素，睾丸激素和二氢睾丸激素结合后转化为有毒物种（DHT）。我们建议确定调节PolyQ-AR介导的毒性和促进我们对SBMA发病机理的分子机制的理解。当前R21应用的主要目的是确定转录共同调节器 AR的介导PolyQ-AR的功能功能获得（GOF）。我们假设两个AR 转录共同调节剂，即蛋白精氨酸甲基转移酶6（PRMT6）和赖氨酸脱甲基酶1（LSD1），协同坐标以增强PolyQ-AR的毒性GOF 改变其转录活动。我们的假设是基于我们的观察结果 AR的翻译修饰（磷酸化和甲基化））是重要的确定剂我们将利用SBMA的特征良好的小鼠模型（转基因AR100Q）和敲入AR113Q小鼠）显示马和谷氨酰胺的长度依赖性神经肌肉无力，肌肉病理学和早期死亡。 SBMA转基因和敲门小鼠代表了研究疾病发病机理和测试药学学的良好模型干涉。我们建议确定PolyQ-AR功能在SBMA中的共同调节剂。我们期望确定在骨骼肌中如何调节AR功能并在SBMA中调节失调。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Skeletal Muscle Pathogenesis in Polyglutamine Diseases.

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。