AT1R-regulated nuclear functions of Gb2

描述(申请人提供)：我们研究计划的长期目标是阐明一种新的分子机制在体内的病理学意义，这可能对调节血管紧张素1型受体(AT1R)过度活动的基因很重要。血管紧张素II(AngII)是肾素-血管紧张素系统影响心血管内稳态的经典介质。这种受体调节AT1R阻滞剂(ARB)靶向的基因表达，ARB是一类广泛使用的抗高血压药物，目前正在试验中用于预防心力衰竭(HF)。ARB抑制血管、肾脏、神经元和心肌细胞的AT1R具有保护作用，但AT1R的不受调节的激活会导致高血压、肾功能衰竭、心肌肥厚和进展为心力衰竭等疾病状态。我们发现了一种新的AT1R信号模式，其中Gaa2？12被动员到细胞核中。在细胞核中，G？2作为基因表达程序的表观遗传调节器发挥作用。因此，G？2？12似乎是一种新的AT1R到核的信使，介导血管紧张素Ⅱ诱导的基因调控。该项目的目标是了解G2功能在核内迄今未知后果的体内意义，这可能有助于靶向治疗。目前，尚不清楚G？2易位在人类疾病状态中是否普遍存在。目前还没有研究核内增强的G？2功能的实验模型，也没有药理学工具来调节G？2与核靶标的相互作用。要克服这些障碍，就需要高风险的创新。这项应用的总体目标是验证这一现象在人类疾病状态下的相关性；开发新的实验模型来研究G？2在核中的作用，并开发小分子来调节G？2的核功能。我们的中心假设是，夸大的G？2核移位有助于持续或“慢性”转录激活，导致病理生理反应。我们将追求以下特定目标：(I)确定G？2在包括人类心力衰竭样本在内的活体疾病模型的核蛋白质组中的相互作用；(Ii)在一种新的转基因小鼠模型中评估增强的G？2功能的病理后果；(Iii)开发用于干扰G？2与转录因子相互作用的小分子探针。如果AT1R活性调节不当，血管紧张素Ⅱ刺激就会变成慢性刺激，损害组织，并导致慢性心肌疾病。清楚地了解新的转录调控机制对于提高ARBS的治疗应用具有重要意义。这些拟议的研究将促进我们对AT1R生物学的了解。

DESCRIPTION (provided by applicant): The long-term goal of our research program is to elucidate the in vivo pathological significance of a novel molecular mechanism, which may be important for the regulation of genes in response to over activity of the angiotensin type 1 receptor (AT1R). Angiotensin II (AngII) is the classical mediator of the effects of the renin- angiotensin system on the cardiovascular homeostasis. This receptor regulates gene expression targeted by the AT1R blockers (ARB), a widely used class of anti-hypertensive drugs that are currently in trial for heart failure (HF) prevention. Inhibition of AT1R in vascular, renal, neuronal and cardiac cells by ARBs protects, but unregulated AT1R activation causes disease states such as hypertension, renal failure, cardiac hypertrophy and progression to HF. We have discovered a novel AT1R signaling paradigm, wherein, Gaa2?12 mobilizes into the nucleus. In the nucleus, G¿2 functions as an epigenetic modulator of gene expression programs. Thus, G¿2?12 appears to function as a novel AT1R-to-nucleus messenger that mediates AngII-induced regulation of genes. The goal of this project is to understand the in vivo significance of hither-to-unknown consequences of G¿2 functions in the nucleus which may be useful for targeted therapy. Currently, it is unknown whether G¿2 translocation is prevalent in human disease states. No experimental models for studying enhanced G¿2 functions in the nucleus exist and there are no pharmacological tools to modulate G¿2 interactions with nuclear targets. To overcome these barriers would require high-risk innovation. The overall objectives of this application are to validate the relevance of the phenomenon in a human disease state; develop new experimental models to study the role of G¿2 in the nucleus and to develop small molecules to modulate nuclear functions of G¿2. Our central hypothesis is that exaggerated nuclear translocation of G¿2 contributes to sustained or "chronic" transcriptional activation leading to pathophysiological responses. We will pursue the following specific aims; (i) Determine interactions of G¿2 in the nuclear proteome of in vivo disease models including human heart failure samples; (ii) Evaluate pathological consequences of enhanced G¿2 function in the nucleus in a novel transgenic mouse model; (iii) Develop small molecule probes for disrupting G¿2 interaction with transcription factors. If the AT1R activity is not regulated properly, AngII stimulus becomes chronic and can damage the tissue, as well as contribute to chronic disorders of myocardium. A clear understanding of novel transcription regulatory mechanisms is important to improve the therapeutic application of ARBs. These proposed studies will advance our knowledge of AT1R biology.