Targeting epigenetic modifiers of androgen receptor activity and toxicity in SBMA

脊髓和延髓肌萎缩症(SBMA)是一种以丧失为特征的神经肌肉疾病。 下层运动神经元和骨骼肌萎缩。SBMA由CAG扩展引起(&gt；38 重复)编码雄激素受体(AR)基因中的多聚谷氨酰胺(PolyQ)链。这个 这种疾病完全表现在男性身上，因为他们的血清中雄激素水平很高。PolyQ-AR 在与雄激素、睾酮和双氢睾酮结合时会转化为有毒物种 (DHT)。 我们建议确定参与调节多聚Q-AR介导的毒性的基因和 促进我们对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 介导多聚Q-AR的毒性功能增益(GOF)。我们假设有两个AR 转录共调控因子，即蛋白精氨酸甲基转移酶6和赖氨酸 去甲基酶1(LSD1)，协同增强PolyQ-AR的毒性GOF，通过 改变其转录活性。我们的假设是基于我们的观察，即- AR的翻译修饰(磷酸化和甲基化)是重要的决定因素 它的毒性。我们将利用特性良好的SBMA(转基因AR100Q)小鼠模型 和敲入AR113Q小鼠)，表现出激素和谷氨酰胺长度依赖 神经肌肉无力、肌肉病理和过早死亡。SBMA转基因和转基因技术 小鼠是研究疾病发病机制和测试药理作用的良好模型 干预。我们建议确定多聚Q-AR的联合调节因子在SBMA中如何发挥作用。我们 希望确定AR功能在骨骼肌中是如何调节的，而在SBMA中是如何调节的。

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.