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，包括肥大、收缩力变化和信号传导改变。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，其风险随着年龄的增长而显着上升。诊断后五年的死亡率在60%到70%之间。与重塑相关的基因表达的变化导致类似于胎儿基因程序的表达谱;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学发展中的作用。蛋白激酶A（PKA）是一种cAMP依赖性蛋白激酶，其磷酸化多个细胞靶标，包括许多转录因子。A-激酶介导蛋白（AKAP）特征性地结合酶的调节II亚基（RII）并将PKA定位于特定底物，导致细胞内的定位信号结构域。PKA依赖性磷酸化的降低与HF相关。最近，在噬菌体展示筛选人心脏PKA结合蛋白的cDNA中，分离出了核蛋白双链蛋白/染色体结构域解旋酶结合蛋白8（Chd 8）的多个重叠克隆。Duplin/Chd 8抑制胚胎小鼠中Wnt和STAT介导的转录，并且与转录阻遏物CTCF一起是染色质绝缘所需的。Duplin/Chd 8已被表征为发育蛋白，但也在成体组织中表达。我们假设，双链蛋白/Chd 8是一种新的AKAP和PKA结合双链蛋白/Chd 8调节抑制转录因子STATS。这种假设的功能的双链蛋白/Chd 8有相关的分子过程的心脏重塑和HF。简单总结：心肌损伤后，心脏中的基因表达发生变化，以模仿发育中观察到的变化;然而，这种适应性反应不会长期维持受损器官，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HF中均受损。本研究将验证核蛋白duplin/Chd 8介导STATS的PKA依赖性调节的假设，探索STATS调节在衰竭心脏中可能出错的潜在机制。