Probing the Cardiac PGC-1 Regulatory Cascade

探索心脏 PGC-1 监管级联

• 批准号: 9032510
• 负责人: DANIEL PATRICK KELLY
• 金额: $ 48.75万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032510
• 关键词: ATP Synthesis Pathway; Adult; Angiotensin II; Biogenesis; Burn injury; Carbon; Cardiac; Cardiac Myocytes; Cardiac development; Cardiomyopathies; Catabolism; Cell Respiration; Chronic; Chronic stress; Contractile Proteins; Development; Disease; Early treatment; Energy Metabolism; Event; Exhibits; Family; Funding; Gene Expression; Gene Targeting; Genes; Glucose; Goals; Health; Heart; Heart Hypertrophy; Heart failure; Human; Hypertrophy; Inborn Genetic Diseases; Infusion procedures; Magnetic Resonance Spectroscopy; Metabolic; Metabolism; Mitochondria; Modality; Modeling; Molecular; Molecular Profiling; Mus; Myocardial; NR4A1 gene; Nuclear Orphan Receptor; Nuclear Receptors; Oxidative Phosphorylation; PPAR gamma; Pathway interactions; Phenotype; Phenylephrine; Physiological Adaptation; Prevention; Process; Production; Pump; Regulation; Regulatory Pathway; Rodent; Role; Route; Signal Transduction; Skeletal Muscle; Staging; Stress; Surveys; Testing; Transcription Coactivator; Ventricular Function; Wild Type Mouse; biological adaptation to stress; design; end stage disease; estrogen-related receptor; fatty acid oxidation; fetal; global health; glucose uptake; hemodynamics; inorganic phosphate; loss of function; member; metabolomics; mitochondrial dysfunction; mitochondrial metabolism; mouse model; novel; postnatal; pressure; programs; response; therapeutic target

DESCRIPTION (provided by applicant): Current treatment modalities for heart failure (HF) are aimed largely at late-stage disease, and do not target primary disturbances in the cardiac myocyte. Increasing evidence indicates that derangements in myocardial fuel catabolism and ATP production contribute to the pathological remodeling en route to HF. This renewal proposal builds upon our long-term pursuit of delineating the molecular regulatory mechanisms that control myocardial fuel metabolism and mitochondrial function in the normal and failing heart. Our previous studies have identified a transcriptional regulatory cascade downstream of the inducible transcriptional co-regulators, PPARgamma coactivator 1 (PGC-1) alpha and beta. We demonstrated that PGC-1alpha and beta are necessary for high level of expression of genes involved in cardiac myocyte mitochondrial energy transduction. Studies conducted over the current funding period used both candidate (PGC-1α/ß-deficient mice) and unbiased molecular profiling strategies to further define the events that are involved in the development of energy metabolic derangements in early stages of heart failure in mice. The results of these studies have led us to hypothesize that the adult mammalian heart is capable of remarkable energy metabolic plasticity in the context of chronic pathophysiological stress such as pressure overload. In support of this hypothesis, we have identified two new gene regulatory pathways that function independent of PGC-1 signaling to control cardiac myocyte energy utilization pathways in the context of mitochondrial dysfunction, such as occurs in the failing heart. The first candidate is the stress-induced nuclear receptor NR4A1 (NUR77). Our preliminary results indicate that NR4A1, and the related factor NR4A3 (NOR1), serve as stress inducible transcriptional regulators of cardiac myocyte glucose utilization. The second candidate is the estrogen-related receptor gamma (ERRgamma). We have found that ERRgamma is capable of inducing the expression of a broad array of genes involved in mitochondrial energy transduction and ATP synthesis. In addition, ERRgamma activates the expression of genes involved in cardiac myocyte differentiation including adult contractile protein genes, a program that could oppose the classic "fetal switch" of HF. This proposal is designed to test the hypothesis that the adult mammalian heart is capable of adaptive energy metabolic re-programming via gene regulatory pathways downstream of NR4A1 and ERRgamma. In Aim 1, we will further delineate and compare NR4A1 and NR4A3 target genes and pathways in heart. In Aim 2, cardiac gene targets and pathways downstream of the estrogen-related receptor gamma (ERRgamma) will be defined. Aim 3 is designed to explore the roles of NR4A1/NR4A3 and ERRgamma in the normal, hypertrophied, and failing heart using gene-targeted NR4A1/3 or ERRgamma loss-of-function mice. The long-term goal of this project is to identify metabolic modulator therapeutic targets relevant to the treatment of early stage heart failure.

描述（由适用提供）：当前的心力衰竭治疗方式（HF）主要针对后期疾病，并且不针对心肌细胞中的主要障碍。越来越多的证据表明，心肌燃料分解代谢和ATP产生的进化有助于在通往HF的途中进行病理重塑。这项更新提案是基于我们长期追求描述的分子调节机制，这些机制控制着心肌燃料代谢和心脏衰竭的线粒体功能。我们以前的研究已经确定了可诱导转录共调节剂PPARGAMMA共激活因子1（PGC-1）alpha和Beta的转录调节级联反应。我们证明了PGC-1Alpha和beta对于高水平的心肌细胞线粒体能量翻译的基因表达是必要的。在当前资金期间进行的研究都使用了候选者（PGC-1α/ß缺陷小鼠）和无偏的分子谱分析策略，以进一步定义小鼠心力衰竭早期能量代谢进化的事件。这些研究的结果使我们假设成年哺乳动物心脏能够在慢性病理生理压力（例如压力过载）的背景下具有显着的能量代谢可塑性。为了支持这一假设，我们已经确定了在线粒体功能障碍的背景下，与PGC-1信号传导无关的两种新基因调节途径，以控制心肌细胞能量利用途径，例如在失败的心脏中发生。第一个候选者是应力诱导的核受体NR4A1（NUR77）。我们的初步结果表明，NR4A1和相关因子NR4A3（NOR1）是心肌细胞葡萄糖利用率的应激诱导的转录调节剂。第二个候选者是与雌激素相关的受体伽马（Errgamma）。我们发现，Errgamma能够诱导参与线粒体能量转移和ATP合成的广泛基因的表达。此外，Errgamma激活了与心肌细胞分化有关的基因的表达，包括成人收缩蛋白基因，该程序可能会反对HF的经典“胎儿转换”。该建议旨在检验以下假设：成年哺乳动物心脏能够通过NR4A1和Errgamma的基因调节途径进行适应性能量代谢重新编程。在AIM 1中，我们将进一步描述并比较心脏中的NR4A1和NR4A3靶基因和途径。在AIM 2中，将定义与雌激素相关受体伽马（Errgamma）下游的心脏基因靶标和途径。 AIM 3旨在探索使用基因靶向基因的NR4A1/3或Errgamma功能丧失的小鼠，探索NR4A1/NR4A3和Errgamma在正常，肥大且失败的心脏中的作用。该项目的长期目标是确定与早期心力衰竭治疗有关的代谢调节剂治疗靶标。