AT1R-regulated nuclear functions of Gb2

AT1R 调节的 Gb2 核功能

基本信息

批准号：
8182771
负责人：
Sadashiva S Karnik
金额：
$ 23.55万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8182771
关键词：
Accounting Angiotensin II Angiotensin II Type 1 Receptor Blockers Angiotensin Receptor Angiotensins Antihypertensive Agents Binding Biological Assay Biology Blood Vessels Calcineurin Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell Nucleus Cell membrane Cells Chromatin Chronic Chronic Disease Cytoplasm Disease Disease Progression Disease model Dissociation Drug Delivery Systems Epigenetic Process Epithelial Evaluation Event Experimental Models G alpha q Protein G-Protein-Coupled Receptors GTP-Binding Proteins Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Growth HDAC5 gene Heart Heart Hypertrophy Heart failure Homeostasis Hormones Human Hypertension Hypertrophy Immunoprecipitation Intervention Kidney Kidney Failure Knock-in Mouse Knowledge Ligands Link Luciferases Mediating Mediator of activation protein Molecular Myocardium Neonatal Neurons Nuclear Nuclear Translocation Pathology Physiology Prevention Protein Subunits Proteins Proteome Public Health Receptor Activation Receptor Signaling Receptor, Angiotensin, Type 1 Regulation Regulator Genes Renin-Angiotensin System Reporter Research Role STAT3 gene Sampling Signal Pathway Signal Transduction Smooth Muscle Myocytes Stimulus Therapeutic Tissues Toxic effect Transcriptional Activation Transgenic Mice Transgenic Model Transgenic Organisms Tyrosine base cell growth cell type chromatin remodeling genome-wide high risk human disease improved in vivo innovation kidney vascular structure mouse model mutant novel prevent programs receptor response small molecule tissue preparation tool transcription factor

项目摘要

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.

描述（由申请人提供）：我们研究计划的长期目标是阐明一种新的分子机制的体内病理学意义，这对于响应血管紧张素1型受体过度活跃的基因调节可能很重要（ AT1R)。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。该受体调节 AT1R 靶向的基因表达。受体阻滞剂 (ARB) 是一类广泛使用的抗高血压药物，目前正在试验用于预防心力衰竭 (HF)。ARB 抑制血管、肾、神经元和心肌细胞中的 AT1R 可以起到保护作用，但不受调节的 AT1R 会导致激活疾病状态。例如高血压、肾功能衰竭、心脏肥大和进展为心力衰竭。我们发现了一种新的 AT1R 信号传导范例，因此，Gaa2?12 动员到细胞核中，G¿。 2 作为基因表达程序的表观遗传调节剂。 2?12 似乎充当一种新型 AT1R 至细胞核的信使，介导 AngII 诱导的基因调节。该项目的目标是了解 G¿ 迄今为止未知的后果的体内意义。 2 细胞核中可能对靶向治疗有用的功能目前尚不清楚。 2 易位在人类疾病状态中普遍存在，没有用于研究增强 G¿ 的实验模型。细胞核中存在 2 种功能，并且没有药理学工具来调节 G¿ 2 与核靶标的相互作用需要高风险的创新，该应用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 在细胞核中并开发小分子来调节 G¿ 2. 我们的中心假设是 G¿ 的夸大核易位2 有助于持续或“慢性”转录激活，从而导致病理生理反应。我们将追求以下具体目标： (i) 确定 G¿ 的相互作用； 2 在体内疾病模型的核蛋白质组中，包括人类心力衰竭样本；(ii) 评估增强 G¿ 的病理后果； 2 在新型转基因小鼠模型中的细胞核中发挥作用；(iii) 开发用于破坏 G¿ 的小分子探针2 与转录因子的相互作用。如果 AT1R 活性没有得到适当的调节，AngII 刺激就会变成慢性的，并可能损害组织，并导致慢性心肌疾病。清楚地了解新的转录调节机制对于改善治疗应用非常重要。这些拟议的研究将增进我们对 AT1R 生物学的了解。公共健康相关性：血管活性激素 AngII 的血管紧张素 1 型受体 (AT1R) 是血管紧张素受体阻滞剂 (ARB) 靶向的基因表达调节剂，ARB 是一类抗高血压药物，ARB 抑制 AT1R 可以预防这种情况。不受调节的 AT1R 激活会导致高血压、肾衰竭、心脏肥大和进展为心力衰竭等疾病状态。范式，因此，G¿ 2?12 动员到细胞核中，G¿ 2 作为基因表达程序的表观遗传调节剂，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的进展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，目前缺乏足够的治疗来逆转这种疾病。