Targeting epigenetic modifiers of androgen receptor activity and toxicity in SBMA

脊髓和延髓肌萎缩症 (SBMA) 是一种神经肌肉疾病，其特征是肌肉萎缩 下运动神经元和骨骼肌萎缩。 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）束。的 该疾病在男性中完全表现出来，因为他们的血清中雄激素水平很高。聚Q-AR 与雄激素、睾酮和二氢睾酮结合后转化为有毒物质 （双氢睾酮）。 我们建议鉴定参与调节polyQ-AR介导的毒性的基因和 增进我们对 SBMA 发病机制的分子机制的理解。 当前 R21 应用的主要目标是确定转录共调控因子 AR介导polyQ-AR的毒性功能获得（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 (PRMT6) 和赖氨酸 去甲基化酶 1 (LSD1) 协同作用，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 AR 的翻译修饰（磷酸化和甲基化）是重要的决定因素 的毒性。我们将利用已充分表征的 SBMA 小鼠模型（转基因 AR100Q 和敲入 AR113Q 小鼠）显示激素和谷氨酰胺长度依赖性 神经肌肉无力、肌肉病理学和过早死亡。 SBMA转基因和基因敲入 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 PolyQ-AR 的协同调节器如何在 SBMA 中发挥作用。我们 期望确定 AR 功能如何在骨骼肌中受到调节以及在 SBMA 中如何失调。

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.