Duplin: A Novel A-Kinase Anchoring Protein

Duplin：一种新型 A 激酶锚定蛋白

• 批准号: 7484816
• 负责人: MAUREEN E O'DONNELL
• 金额: $ 2.79万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7484816
• 关键词: A kinase anchoring protein; AKAP13 gene; Adrenergic Agonists; Adult; Affect; Age; American; Amino Acids; Binding; Binding Proteins; Binding Sites; Biological Assay; Cardiac; Cardiac Myocytes; Cell Line; Cells; Chinese Hamster Ovary Cell; Chromatin; Complementary DNA; Condition; Critical Pathways; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Diagnosis; Embryo; Enzymes; Epigenetic Process; Figs - dietary; Gene Expression; Gene Proteins; Genes; Genetic Transcription; Heart; Heart failure; Human; Hypertrophy; Injury; Lead; Light; Localized; Luciferases; Measures; Mediating; Molecular; Molecular Profiling; Mus; Muscle Cells; Mutagenesis; Myocardial; Myocardium; Neonatal; Nuclear; Nuclear Protein; Nuclear Proteins; Numbers; Object Attachment; Organ; Pathology; Phage Display; Phosphorylation; Phosphotransferases; Play; Process; Protein Binding; Protein Kinase A Inhibitor; Proteins; Rattus; Regulation; Reporter; Risk; Risk Assessment; Role; STAT3 gene; Screening procedure; Signal Transduction; Stress; Testing; Tissues; Transcriptional Activation; Transducers; cardiogenesis; cellular targeting; chromatin remodeling; design; fetal; helicase; in vivo; inhibitor/antagonist; injured; mortality; mutant; novel; programs; promoter; response; transcription factor

DESCRIPTION (provided by applicant): Following injury to the heart, the myocardium undergoes adaptive changes including hypertrophy, changes in contractility, and altered signaling. This process of 'cardiac remodeling' can ultimately lead to heart failure (HF), which is estimated to affect two percent of Americans, risk for which rises significantly with age. Mortality five years post-diagnosis is between sixty and seventy percent. Changes in gene expression associated with remodeling result in an expression profile similar to the fetal gene program; therefore, understanding normal development of the heart may shed light on the role of fetal genes in the development of heart pathology. Protein Kinase A (PKA) is a cAMP-dependent protein kinase that phosphorylates multiple cellular targets, including a number of transcription factors. A-Kinase Anchoring Proteins (AKAPs) characteristically bind the regulatory II subunits (Rll) of the enzyme and localize PKA to specific substrates, resulting in localized signaling domains within the cell. Decreased PKA-dependent phosphorylation is associated with HF. Multiple overlapping clones of the nuclear protein duplin/chromodomain helicase binding protein 8 (Chd8) were recently isolated in phage display screening of human heart cDNA for PKA binding proteins. Duplin/Chd8 inhibits Wnt and STATS-mediated transcription in the embryonic mouse, and is required for chromatin insulation in conjunction with the transcription represser CTCF. Duplin/Chd8 has been characterized as a developmental protein, but is also expressed adult tissue. We hypothesize that duplin/Chd8 is a novel AKAP and that PKA bound to duplin/Chd8 modulates inhibition of the transcription factor STATS. This hypothesized function of duplin/Chd8 has relevance to the molecular processes underlying cardiac remodeling and HF. Lay Summary: Following myocardial injury, gene expression in the heart changes to mimic that observed in development; however, this adaptive response does not long sustain the injured organ, and this condition can quickly deteriorate into heart failure (HF). The cell signaling kinase protein kinase A (PKA) and the transcription factor STATS are both compromised in HF. This study will test the hypothesis that the nuclear protein duplin/Chd8 mediates PKA-dependent regulation of STATS, exploring a potential mechanism by which STATS regulation could go awry in the failing heart.

描述（由申请人提供）：心脏损伤后，心肌发生适应性变化，包括肥厚、收缩性改变和信号改变。这种“心脏重塑”的过程最终会导致心力衰竭（HF），据估计，2%的美国人患有心力衰竭，其风险随着年龄的增长而显著上升。确诊后5年的死亡率在60%到70%之间。与重塑相关的基因表达变化导致与胎儿基因程序相似的表达谱；因此，了解心脏的正常发育可能会揭示胎儿基因在心脏病理发展中的作用。蛋白激酶A （PKA）是一种camp依赖性蛋白激酶，可磷酸化多种细胞靶标，包括许多转录因子。a -激酶锚定蛋白（AKAPs）结合酶的调控II亚基（Rll）并将PKA定位到特定的底物上，从而在细胞内产生局部的信号域。pka依赖性磷酸化降低与HF有关。近年来，在人类心脏PKA结合蛋白cDNA噬菌体展示筛选中，分离到了核蛋白双蛋白/染色质结构域解旋酶结合蛋白8 （Chd8）的多个重叠克隆。在胚胎小鼠中，Duplin/Chd8抑制Wnt和stats介导的转录，并且与转录抑制因子CTCF一起是染色质绝缘所必需的。Duplin/Chd8被认为是一种发育蛋白，但也在成人组织中表达。我们假设duplin/Chd8是一种新的AKAP， PKA结合到duplin/Chd8上调节转录因子STATS的抑制。双重蛋白/Chd8的这种假设功能与心脏重构和心衰的分子过程有关。摘要：心肌损伤后，心脏中基因表达的变化与发育过程中观察到的相似；然而，这种适应性反应不能长期维持受损器官，这种情况会迅速恶化为心力衰竭（HF）。细胞信号激酶蛋白激酶A （PKA）和转录因子STATS均在HF中受损。本研究将验证核蛋白duplin/Chd8介导pka依赖性STATS调控的假设，探索衰竭心脏中STATS调控出错的潜在机制。