Duplin: A Novel A-Kinase Anchoring Protein

Duplin：一种新型 A 激酶锚定蛋白

• 批准号: 7676742
• 负责人: MAUREEN E O'DONNELL
• 金额: $ 2.82万
• 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 2011-05-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676742
• 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; 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; Luciferases; Measures; Mediating; Molecular; Molecular Profiling; Mus; Muscle Cells; Mutagenesis; Myocardial; Myocardium; Neonatal; Nuclear; Nuclear Protein; Nuclear Proteins; 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）：心脏受伤后，心肌发生适应性变化，包括肥大，收缩力的变化和信号变化。这种“心脏重塑”的过程最终会导致心力衰竭（HF），据估计，这会影响2％的美国人，随着年龄的增长，这种风险大大增加。诊断后五年死亡率在60％至70％之间。与重塑相关的基因表达的变化导致表达谱类似于胎儿基因程序。因此，了解心脏的正常发育可能会阐明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）特征在于酶的调节II亚基（RLL），并将PKA定位于特定底物，从而导致细胞内的局部信号域。 PKA依赖性磷酸化降低与HF相关。最近，在PKA结合蛋白的噬菌体显示筛选中分离出核蛋白Duplin/Chromodomain结合蛋白8（CHD8）的多个重叠的克隆（CHD8）。 DUPLIN/CHD8抑制Wnt和STAT介导的胚胎小鼠的转录，并且是染色质绝缘层与转录阻遏物CTCF所必需的。 Duplin/CHD8已被描述为发育蛋白，但也表达成人组织。我们假设Duplin/CHD8是一种新型的AKAP，并且与Duplin/CHD8结合的PKA调节了对转录因子统计数据的抑制。 Duplin/CHD8的这种假设功能与心脏重塑和HF的分子过程相关。摘要摘要：在心肌损伤之后，心脏中基因表达在发育中观察到的模仿变化；但是，这种适应性反应并不长期维持受伤的器官，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）和转录因子统计均受到HF的损害。这项研究将检验以下假设：核蛋白DUPLIN/CHD8介导了PKA依赖性统计的调节，探索了一种潜在的机制，该机制通过该机制可能会在失败的心脏中脱颖而出。