调控衰老的关键表观遗传改变及重要信号通路

项目名称： 调控衰老的关键表观遗传改变及重要信号通路

项目编号： No.81330009

项目类型： 重点项目

立项/批准年度： 2014

项目学科： 医药、卫生

项目作者： 周中军

作者单位： 香港大学深圳研究院

项目金额： 290万元

中文摘要： 衰老是各种老年疾病的最大危险因子。衰老过程缓慢而复杂，伴随大量基因表达改变与信号通路紊乱。衰老的渐进性导致很难区分诱导衰老的重要信号以及衰老过程伴随的基因表达的改变。研究单一基因突变导致的快速衰老对理解复杂的衰老具有重要提示。研究表明，导致儿童早老症的早老素在正常衰老过程显著上升，而且两者间有共同的特定表观遗传学改变，提示早老与衰老具有共同的分子机制。本课题通过研究不同早老动物模型（Zmpste24-/-；Klotho-/-），结合人类早老症(HGPS)及正常衰老，寻求调控衰老的关键基因及重要信号通路的改变，从信号通路，表观遗传以及基因组稳定三个方面深入探讨衰老分子机制。通过有针对性的干预延缓衰老，延长健康寿命。为延缓并降低老年疾病的发生，提高老年人群健康寿命提供重要依据。

中文关键词： 细胞衰老;信号传导;表观遗传学;儿童早老症;Klotho

英文摘要： Aging is the biggest risk factor for various aging-associated diseases. Aging is characterized by gradual decline of physiological functions and fertility in response to various environmental or endogenous stresses. Aging processes progress slowly over a long period of time associated with various alterations in gene expression and epigenetics, making it difficult to distinguish changes that trigger aging from those altered by aging/senescence. Human premature aging syndromes caused by mutations in a particular gene provide excellent tools for dissecting the complex aging processes into simpler events triggered by defined molecules. Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder of early onset premature aging, predominantly caused by partially processed truncated prelamin A termed progerin. Mice deficient in Zmpste24, a metalloproteinase responsible for prelamin A processing, exhibit progeroid features found in HGPS. It has been shown that low level of progerin is expressed in cells from normal individuals and level of progerin increases along aging. In addition, similar epigenetic alterations were observed in specific histone modifications in both HGPS and normal aging, suggesting a possible paralleled molecular mechanism between premature aging and normal aging. Taking advantages of two independent premature aging mouse models, we propose to systematically profile and compare alterations in epigenetics, transcription and genome maintenance among normal aging, human HGPS and premature aging mouse models (Zmpste24 deficient and Klotho deficient mice). We aim to identify critical genes/signaling pathways driving aging processes. We hope to delay the onset of aging and extend the healthspan by targeting the key regulatory pathways of aging. This work will provide fundamental knowledge of aging and to significantly decrease the risk for aging associated disease in elderly.

英文关键词： Cellular Senescence;Signaling Transduction;Epigenetics;HGPS;Klotho