Targeting epigenetic modifiers of androgen receptor activity and toxicity in SBMA

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。

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.