AT1R-regulated nuclear functions of Gb2

描述（由申请人提供）：我们的研究计划的长期目标是阐明一种新的分子机制的体内病理意义，这可能对调节血管紧张素1型受体（AT1R）过度活性的基因很重要。血管紧张素II （AngII）是肾素-血管紧张素系统对心血管稳态影响的经典介质。这种受体调节AT1R阻滞剂（ARB）靶向的基因表达，ARB是一种广泛使用的抗高血压药物，目前正处于预防心力衰竭（HF）的试验中。ARBs可抑制血管、肾脏、神经元和心脏细胞中的AT1R，但不受调节的AT1R激活可导致高血压、肾功能衰竭、心脏肥厚和HF进展等疾病状态。我们发现了一种新的AT1R信号范式，其中Gaa2？12动员进入细胞核。在细胞核中，G¿2作为基因表达程序的表观遗传调节剂。因此,G 2 ?12似乎作为一种新的at1r到核信使，介导血管i诱导的基因调节。该项目的目标是了解迄今为止未知的G¿2功能在细胞核中的体内意义，这可能对靶向治疗有用。目前，尚不清楚G¿2易位是否在人类疾病状态中普遍存在。目前还没有研究核中G¿2功能增强的实验模型，也没有药物工具来调节G¿2与核靶标的相互作用。要克服这些障碍，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核易位有助于持续或“慢性”转录激活，导致病理生理反应。具体目标是：(i)确定G¿2在包括人类心力衰竭样本在内的体内疾病模型的核蛋白质组中的相互作用；（ii）在一种新型转基因小鼠模型中评估核中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活性调节不当，AngII刺激会变成慢性刺激，对组织造成损伤，并导致慢性心肌疾病。清楚地了解新的转录调控机制对提高arb的治疗应用至关重要。这些拟议的研究将促进我们对AT1R生物学的认识。

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.