AT1R-regulated nuclear functions of Gb2

描述（由申请人提供）：我们研究项目的长期目标是阐明一种新分子机制的体内病理学意义，该机制可能对血管紧张素1型受体（AT1R）过度活性的基因调节很重要。血管紧张素II（AngII）是肾素-血管紧张素系统影响心血管稳态的经典介质。该受体调节AT1R阻滞剂（ARB）靶向的基因表达，ARB是一种广泛使用的抗高血压药物，目前正在试验预防心力衰竭（HF）。ARB抑制血管、肾脏、神经元和心脏细胞中的AT1R可起到保护作用，但AT1R活化不受调节可导致疾病状态，如高血压、肾衰竭、心脏肥大和进展为HF。我们已经发现了一种新的AT1R信号模式，其中，Gaa2？12号进入细胞核。在细胞核中，G <$2作为基因表达程序的表观遗传调节剂发挥作用。因此，G2？12似乎作为一种新的AT1R到核信使，介导AngII诱导的基因调控。该项目的目标是了解细胞核中G2功能的迄今未知后果的体内意义，这可能对靶向治疗有用。目前，尚不清楚G2易位是否在人类疾病状态中普遍存在。目前还没有研究细胞核中G <$2功能增强的实验模型，也没有药理学工具来调节G <$2与核靶点的相互作用。克服这些障碍需要高风险的创新。本申请的总体目标是验证该现象在人类疾病状态中的相关性;开发新的实验模型来研究G <$2在细胞核中的作用，并开发小分子来调节G <$2的核功能。我们的中心假设是，夸张的核易位G <$2有助于持续或"慢性"转录激活，导致病理生理反应。我们将追求以下具体目标：（i）确定G <$2在体内疾病模型（包括人类心力衰竭样本）的核蛋白质组中的相互作用;（ii）评估新型转基因小鼠模型中细胞核中G <$2功能增强的病理后果;（iii）开发用于破坏G <$2与转录因子相互作用的小分子探针。如果AT1R活性没有得到适当的调节，AngII刺激会变成慢性的，并且会损害组织，以及导致心肌的慢性疾病。清楚地了解新的转录调控机制对于提高ARB的治疗应用非常重要。这些拟议的研究将推进我们对AT1R生物学的认识。 公共卫生相关性：血管活性激素AngII的血管紧张素1型受体（AT1R）是一类抗高血压药物血管紧张素受体阻滞剂（ARB）靶向的基因表达调节剂。ARB对AT1R的抑制可预防，但不受调节的AT1R激活可导致疾病状态，如高血压、肾衰竭、心脏肥大和进展为心力衰竭。我们已经发现了一种新的AT1R信号模式，其中，G？2？12号进入细胞核。在细胞核中，G <$2作为基因表达程序的表观遗传调节剂发挥作用。在这项提案中，我们将研究与疾病状态相关的转录的新型表观遗传控制。这些研究对于了解心血管疾病进展的机制和确定新的干预药物靶点是必要的。心血管疾病造成的死亡仍然是一个公共卫生问题，目前缺乏扭转这种情况的适当治疗。

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. PUBLIC HEALTH RELEVANCE: The angiotensin type 1 receptor (AT1R) for the vasoactive hormone AngII is a regulator of gene expression targeted by the angiotensin receptor blockers (ARB), a class of anti-hypertensive drugs. Inhibition of AT1R by ARBs protects against, but unregulated AT1R activation causes disease states such as hypertension, renal failure, cardiac hypertrophy and progression to heart failure. We have discovered a novel AT1R signaling paradigm, wherein, G¿2?12 mobilizes into the nucleus. In the nucleus, G¿2 functions as an epigenetic modulator of gene expression programs. In this proposal we will be investigating the novel epigenetic control of transcription linked to disease states. These studies are necessary to understand mechanisms of progression of cardiovascular diseases, and to identify new drug targets for intervention. Fatalities from cardiovascular diseases remain a public health concern and adequate treatment for their reversal is currently lacking.