靶向抑制炎性老化预防老化相关性疾病的机制研究

The aging process is driven by interrelated mechanisms that lead to the emergence of characteristic phenotypes that include multi-organ damage. Uncovering the mainstream mechanism of aging requires a profound understanding of the molecular, cellular and physiological mechanisms that ultimately determine functional changes. In this context, the inflammatory state of aging (inflammageing) plays a major role. Longitudinal studies have shown that with aging most individuals tend to develop a chronic low-grade proinflammatory state, and that such a state is a strong risk factor for multimorbidity, physical and cognitive disability, frailty and death. Recently, a series of investigations have demonstrated that adipose tissue dysfunction, which leads to adipose tissue inflammation, plays an important role in modifying the inflammatory state in aging. Therefore, attenuating adipose tissue inflammation has become a current focus in the ongoing fight against aging and aging-associated disorders. Our previous study investigated that 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an amplifier of local glucocorticoid activity, led to a significant inhibition of the inflammatory state in white adipocyte, indicating that 11β-HSD1 acts as a vital regulator that controls the adipose tissue inflammation. Furthermore, we observed a striking improvement of cardiac remolding and attenuation of cardiac hypertrophy in BVT.2733 (a selective inhibitor of 11β-HSD1)-treated rats. Moreover, osteoblast function also regulated by 11β-HSD1 which is a underlying mechanism of osteoporosis. Therefore, 11β-HSD1 might play a key role in aging related diseases via controlling the inflammatory state in adipose tissue. In this proposal, we synthesized the specific 11β-HSD1 inhibitor targeted adipose tissue, which was already synthesized, to clarify the role of 11β-HSD1 in regulating the fat inflammation and provide therapeutic target for aging-associated disorders.

老化是一个多系统、多器官功能衰退的过程。“炎性老化”（慢性系统性低度炎症）是老化相关性疾病的核心，是多器官功能衰退的共同基石，也是慢性应激的病理基础。而脂肪组织是系统性炎症的主要来源，也是调控代谢与老化的重要器官。我们前期研究发现，作为调节应激激素（糖皮质激素）活性的关键酶，11β-羟化类固醇脱氢酶1（11β-HSD1）调控脂肪炎症，在老化相关性疾病（骨质疏松、心肌肥大）中也发挥重要作用。因而我们假说，11β-HSD1通过诱发脂肪组织炎症促进机体老化，引起一系列老化相关性疾病。本课题利用特异性脂肪组织靶向11β-HSD1抑制剂（已自行合成），研究其对老化相关性疾病的影响。并在特异性脂肪组织11β-HSD1敲除小鼠模型中应用脂肪手术移植技术，从脂肪组织到远端靶器官（骨骼肌，心肌，骨骼，肾脏），搞清11β-HSD1通过调控脂肪炎症影响多器官功能的分子机理，为有效预防老化相关性疾病提供新手段。

老化是一个多系统、多器官功能衰退的过程。“炎性老化”（慢性系统性低度炎症）是老化相关性疾病的核心，是多器官功能衰退的共同基石，也是慢性应激的病理基础。而脂肪组织是系统性炎症的主要来源，也是调控代谢与老化的重要器官。我们前期研究发现，作为调节应激激素（糖皮质激素）活性的关键酶，11β-羟化类固醇脱氢酶1（11β-HSD1）调控脂肪炎症，在老化相关性疾病（骨质疏松、心肌肥大）中也发挥重要作用。因而我们假说，11β-HSD1通过诱发脂肪组织炎症促进机体老化，引起一系列老化相关性疾病。本课题利用特异性脂肪组织靶向11β-HSD1抑制剂（已自行合成），研究其对老化相关性疾病的影响。并在特异性脂肪组织11β-HSD1敲除小鼠模型中应用脂肪手术移植技术，从脂肪组织到远端靶器官（骨骼肌，心肌，骨骼，肾脏），搞清11β-HSD1通过调控脂肪炎症影响多器官功能的分子机理，为有效预防老化相关性疾病提供新手段。