CREG1介导脂源性外泌体发生改善衰老性心肌纤维化重构的作用及机制研究

慢性心力衰竭（CHF）是与老龄化并行的终末期心血管疾病。心肌纤维化重构是心脏衰老的主要病理特征，但衰老性心肌纤维化的发生机制远未阐明。从多器官老化互作调控入手，寻找衰老性心肌纤维化重构发生的早期调控机制和治疗分子，对CHF防治具有重要意义。新近研究发现，脂肪组织老化与衰老性心肌纤维化重构发生密切相关。并且，脂肪蛋白质组学研究提示：作为广泛表达的分化稳态调控蛋白，CREG1在脂肪组织中表达缺失可能参与了衰老性心肌重构发生。为检验这一假说，本研究拟构建脂肪组织Creg1基因特异性敲除的衰老小鼠模型，阐明CREG1缺失在脂肪组织老化和衰老性心肌纤维化重构中的作用，并通过体外组织学和细胞学研究阐明其外泌体调控的分子机制。进一步应用脂肪组织特异性转Creg1基因小鼠或外泌体发生干预进行衰老性心肌纤维化重构的在体保护研究。

Chronic heart failure (CHF) is an end-stage cardiovascular disease in parallel with aging. Myocardial fibrosis remodeling is the main pathological feature of cardiac aging, but the mechanism of senile myocardial fibrosis is far from elucidated. Starting from the multi-organ aging interaction regulation, it is of great significance to find the early regulation mechanism and therapeutic molecules of aging myocardial fibrosis remodeling. Recent studies have found that aging of adipose tissue is involved in the occurrence of aging myocardial fibrosis. Furthermore, fat proteomics studies suggest that as a widely expressed differentiation homeostasis regulatory protein, the loss of CREG1 expression in adipose tissue may be involved in the occurrence of aging myocardial fibrosis remodeling. To test this hypothesis, this study proposes to construct an aging model of Creg1 gene-specific knockout mice in adipose tissue, and to elucidate the mechanism of CREG1 deletion mediating the adipose tissue-induced myocardial fibrosis remodeling. The study clarifies the study of the mechanism of exosomes and finds new therapeutic targets for senile myocardial fibrosis. Further study in vivo using adipose tissue-specific Creg1 transgenic mice or exosomes to improve senile myocardial fibrosis remodeling.