The role of non-canonical WNT signaling in the development of atrial cardiomyopathy and atrial fibrillation

非经典 WNT 信号传导在心房心肌病和心房颤动发展中的作用

• 批准号: 534358899
• 负责人: Fabienne Kreimer
• 金额: --
• 依托单位: Broad Institute of MIT and Harvard
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/534358899?language=en
• 关键词: role; non; canonical; WNT; signaling

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia with a rapidly growing prevalence that is expected to double in the next 30 years. The consequences of AF include higher rates of stroke, dementia, and congestive heart failure, and AF is even associated with increased mortality. New therapeutic options, particularly those with unique mechanisms of action, are needed to improve the treatment of patients with AF. Genetic studies of AF have identified a single nucleotide polymorphism (SNP) near the transcription factor ZFHX3 as the second most strongly associated gene variant. The SNP was found to modulate an enhancer that regulates ZFHX3 expression, and decreased ZFHX3 expression was found to increase the risk of AF. Cardiac Zfhx3 deficiency in mice has been shown to lead to early atrial structural/electrical pathology and eventually cardiomyopathy. WNT proteins are highly conserved growth factors that regulate cellular processes such as gene transcription, cell proliferation, migration, polarity, and division. WNT signaling is essential for cardiac development and is characterized by a canonical and a noncanonical pathway. Upregulation of the noncanonical WNT signaling pathway has been identified as a common and perhaps unifying feature in AF. However, there is a growing body of data suggesting "reactivation" of the WNT pathway in various cardiac diseases, and we suggest that this may be the case in both genetically predisposed and "acquired" AF. SFRP5 is an inhibitory WNT ligand and adipokine with affinity for the non-canonical WNT5a. ZFHX3 has been found to regulate the expression of SFRP5, such that ZFHX3 deficiency leads to increased WNT signaling. We will investigate whether non-canonical WNT inhibition by overexpression of SFRP5 can "rescue" the pathology associated with ZFHX3 knockout. The working hypothesis of the project is that pathological non-canonical WNT signaling contributes to AF susceptibility in both genetic and acquired AF and therefore may be a common pathway that can be exploited for therapeutic purposes.

心房颤动（AF）是最常见的持续性心律失常，患病率迅速增长，预计在未来30年内将翻一番。AF的后果包括中风、痴呆和充血性心力衰竭的发生率较高，AF甚至与死亡率增加有关。需要新的治疗选择，特别是那些具有独特的作用机制，以改善AF患者的治疗。AF的遗传学研究已经确定了转录因子ZFHX 3附近的单核苷酸多态性（SNP）作为第二个最强相关的基因变异。发现SNP调节调节ZFHX 3表达的增强子，并且发现ZFHX 3表达降低会增加AF的风险。小鼠中的心脏ZfHX 3缺陷已被证明会导致早期心房结构/电病理学和最终心肌病。WNT蛋白是高度保守的生长因子，其调节细胞过程，例如基因转录、细胞增殖、迁移、极性和分裂。WNT信号传导对心脏发育至关重要，其特征在于经典和非经典途径。上调的非经典WNT信号通路已被确定为一个共同的，也许是统一的功能，在AF。然而，有越来越多的数据表明“重新激活”的WNT通路在各种心脏疾病，我们认为，这可能是在遗传易感性和“获得性”AF的情况下。SFRP 5是一种抑制性WNT配体和脂肪因子的非经典WNT 5a的亲和力。已经发现ZFHX 3调节SFRP 5的表达，使得ZFHX 3缺陷导致WNT信号传导增加。我们将研究通过SFRP 5过表达的非经典WNT抑制是否可以“拯救”与ZFHX 3敲除相关的病理。该项目的工作假设是，病理性非经典WNT信号传导有助于遗传性和获得性AF中的AF易感性，因此可能是可用于治疗目的的常见途径。