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，心肌会发生适应性变化，包括肥大、收缩力变化和信号传导改变。这种“心脏重塑”的过程最终可能导致心力衰竭（HF），据估计会影响百分之二的美国人，其风险随着年龄的增长而显着增加。诊断后五年的死亡率在百分之六十到百分之七十之间。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有助于了解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，可磷酸化多个细胞靶标，包括许多转录因子。 A-激酶锚定蛋白 (AKAP) 特征性地结合酶的调节 II 亚基 (RII)，并将 PKA 定位到特定底物，从而在细胞内产生定位信号结构域。 PKA 依赖性磷酸化降低与心衰相关。最近在噬菌体展示筛选人心脏 cDNA 的 PKA 结合蛋白中分离出核蛋白 duplin/染色结构域解旋酶结合蛋白 8 (Chd8) 的多个重叠克隆。 Duplin/Chd8 抑制胚胎小鼠中 Wnt 和 STATS 介导的转录，并且与转录抑制子 CTCF 一起是染色质绝缘所必需的。 Duplin/Chd8 已被定性为发育蛋白，但也在成人组织中表达。我们假设 duplin/Chd8 是一种新型 AKAP，并且与 duplin/Chd8 结合的 PKA 调节转录因子 STATS 的抑制。 duplin/Chd8 的这种假设功能与心脏重塑和心力衰竭的分子过程相关。简单总结：心肌损伤后，心脏中的基因表达发生变化，模仿发育过程中观察到的情况；然而，这种适应性反应并不能长期维持受损器官，并且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 在心力衰竭中均受到损害。这项研究将检验核蛋白 duplin/Chd8 介导 PKA 依赖性 STATS 调节的假设，探索 STATS 调节在衰竭心脏中可能出错的潜在机制。