研究细胞/组织器官衰老与机体衰老关联机制的条件性敲入小鼠模型的建立与分析

细胞衰老是机体衰老的原因还是结果？哪些组织器官衰老加速机体老化？这些衰老研究的重大科学问题亟待解决。Lamin A突变（Progerin）加速人体老化，导致HGPS早老症，为衰老研究提供了极具特色的疾病模型。我们过往以全身性基因敲除早衰小鼠为模型，从基因组不稳定性、表观遗传、染色质重塑、干细胞衰老等角度对早老症的致病机制与治疗策略进行了广泛研究。然而，现有全身性敲除模型难以回答“细胞衰老和组织器官退化是机体衰老的因还是果”这一“鸡先还是蛋先”的科学难题。本项目拟构建条件性敲入Progerin（Pro-CKI）小鼠，若借助组织特异的Cre小鼠，可用于研究特定组织器官衰老的分子机制与生理特性，揭示组织器官衰老与机体老化之间的互作机制，验证细胞衰老加速机体衰老这一重大科学假说。我们将举例探讨血管平滑肌或干细胞衰老与机体衰老的关联机制及干细胞抗衰老治疗的可行性。

Aging is a lifetime-long progressive decline of physiological functions, characterized with cellular senescence and reduced tissue regeneration capacity. Understanding the mechanisms of aging will help to lessen the impact of aging population via developing interventions to prevent the development or slow down the progression of age-related diseases, like cardiovascular diseases, type 2 diabetes mellitus and cancer etc. However aging process is rather complicated and many fundamental questions are still poorly understood, like what is the contributing role of cellular senescence during organism aging? Which tissues/organs are critical for organism aging?..Hutchinson-Gilford progeria syndrome (HGPS) caused by a Lamin A mutant, i.e. Progerin, is a rare premature ageing genetic disorder. Patients suffering from HGPS have a mean age of 13.4 years and are clinically characterized with early growth retardation, short stature, lipodystrophy, alopecia, stiff joints, osteoporosis, dilated cardiomyopathy and atherosclerosis. Mouse models harboring the same mutation recapitulates many progeroid features of HGPS. Moreover, low level of progerin is also expressed in normal human cells. The level and the number of positive cells increase along with age-related telomere attrition. Given its close resemblance to normal aging, HGPS is extensively studied during the last decade as an ideal model to understand human aging. Previously, we have found that progeria cells undergo early senescence owing to delayed chromatin remodeling and defective DNA repair (Nature Medicine 2005, PNAS 2011, Nature Communications 2013 and Aging Cell 2013). We found that resveratrol, a small molecule mimic of caloric restriction, enhances mesenchymal stem cell self-renewal, ameliorates premature aging features and extends lifespan in a progeria mouse model (Cell Metabolism 2012). However, studies based on conventional knock-out or knock-in mouse models are difficult to answer basic questions like the causal links between cellular/tissue aging and organism aging. Here we propose to generate a progerin conditional knock-in (Pro-CKI) mouse model. Together with tissue specific Cre transgenic mice, Pro-CKI mice can be used to investigate tissues or organs that are critical for organism aging, and the causal role of cellular senescence in organism aging. In this project, we will take vascular smooth muscle and mesenchymal stem cell aging as examples to investigate their contributions to accelerated aging.