血管内皮与脂肪组织调控衰老的机制研究

人体衰老伴随各种组织器官萎缩与功能性衰退，然而哪些组织器官决定了整体衰老进程尚不明确，不同组织器官之间如何通过对话与互作调控机体衰老更有待研究。人类衰老进程漫长，从伦理上和技术上都不利于研究。LMNA突变导致人类早老症与小鼠快速衰老，为人类衰老机制与临床前干预研究提供了极具特色的疾病与动物模型。本项目在前期基础上，构建了血管内皮与脂肪组织特异衰老小鼠，拟（1）利用系统生物学与候选分子相结合的方法，解析血管内皮、脂肪组织衰老及功能紊乱的分子基础；（2）探讨血管内皮或脂肪组织借助器官对话与互作（包括但不限于血管-骨、脂肪-血管、脂肪-心、脂肪-骨等）调控机体衰老与寿命的机制；（3）利用快速衰老小鼠，采取干细胞治疗与分子药物干预的策略，开展临床前抗衰老研究。预期成果有助于理解衰老的器官对话与互作机制，有望从系统衰老角度为解析心脑血管疾病与代谢性疾病的发病机制与预治等医学难题提供实验依据。

Aging involves a progressive deterioration of physiological functions, i.e. reduced capacity to repair injured organs, increased propensity to infection, decreased fecundity, and predisposition to cancer etc. Despite advances in aging research, fundamental questions still remain, i.e. which tissues or organs are critical for aging and what is the mechnism? ..Hutchinson-Gilford progeria syndrome (HGPS) is a severe premature aging disorder. The phenotypic resemblance of HGPS to normal aging makes it an ideal model to understand the mechanisms of aging. Moreover, transgenic mouse models with Lmna G609G mutation, equivalent to LMNA G608G in humans, recapitulate many progeroid features of HGPS. Here, we generated conditional alleles of LmnaG609G/G609G in mice. This model, together with tissue-specific Cre mice like Tie2-Cre (endothelial cells) and Adipoq-Cre (adipocytes), provides chances to address whether specific tissue(s) or organ(s) are critical for aging, and if yes, the potential mechanisms. In current project, we proposed (1) to make two tissue-specific aging models, i.e. LmnaG609G/G609G;TC mice (endothelium) and LmnaG609G/G609G;AC (adipose tissue) mice, and to understand the molecular mechanisms behind endothelial and adipose senescence; (2) to investigate the systemic mechanisms linking endothelial and adipose senescence to organism aging; (3) to test the anti-aging effects of stem cells (endothelial progenitor cells, EPCs) and anti-inflammatory molecules. ..Aging society is a global problem. The proposed studies will help to better understand mechanisms of aging and to develop interventions that could delay the onset or the progression of age-related diseases. It provides excellent training opportunities and career development path for postdocs and students in the area of aging.