蛋白激酶D1调控衰老相关炎症的机理及其在衰老性疾病中的作用

人体衰老是各种老年病发病的最大危险因素。细胞衰老是器官衰老和整体衰老的基础，也与老年病发病有密切关系。衰老的细胞会分泌各类因子，称为衰老的分泌表型（SASP）。SASP中的炎症因子IL-6和IL-8在衰老相关炎症和老年病中可能有重要作用。蛋白激酶D（PKD）是一类新的丝氨酸/苏氨酸激酶。我们的前期研究表明：在细胞衰老中，PKD1通过ROS-PKCδ-PKD1信号轴调控NF-κB的活性来影响IL-6和IL-8的表达和分泌。在此项目中我们将主要研究：1)鉴定PKD1调控NF-κB活性的直接作用靶点；2)研究SASP的分泌途径和调控机理，探索PKD1介导的从TGN向细胞表面转运和分泌蛋白的信号通路在调控SASP分泌中的作用；3)探索干预PKD1对整体动物寿命和衰老性疾病的影响。此项研究对阐明SASP的调控机理，为找到干预衰老相关炎症和老年病的新靶点，具有重要意义。

Aging is the highest risk factor in the pathophsiology of age-related diseases. Cell senescence is the common basis of organ and human aging, and has been implicated in the pathology of age-related disease. Senescent cells secret many kinds of factors, which is termed as senescence-associated secret phenotype (SASP). Pro-inflammatory cytokines IL-6 and IL-8 in SASP has been proposed to contribute to low-level chronic inflammation that is a hallmark of aged mammalian tissues and may play an important role in many age-related diseases. Protein kinase D (PKD) is a novel serine/threonine kinase. In our preliminary studies we show that PKD1 can regulate IL-6 and IL-8 expression and secretion via modulation of NF-κB activity in cell senescence. We also show that ROS-PKCδ-PKD1 axis is essential for the initiation and maintenance of IL-6 and IL-8 expression. In this study, we will 1) identify the direct target of PKD1 to regulate NF-kB activity; 2)study the mechanism of SASP secretion, and investigate the possible involvment and role of PKD1-mediated protein transport pathway from TGN to cell surface in SASP secretion; 3)investigate the possible role of PKD1 in age and age-related diseases by intervention of PKD1. Thus, this study has important significance in elucidating the mechanism of SASP secretion, and may provide the new target for the intervention of senescence-associated inflammation and age-related diseases.