灵长类增龄相关健康状态减损的生物学基础

项目来源

国家重点研发计划(NKRD)

项目主持人

曲静

项目受资助机构

中国科学院动物研究所

立项年度

2018

立项时间

未公开

项目编号

2018YFC2000100

研究期限

未知 / 未知

项目级别

国家级

受资助金额

3865.00万元

学科

主动健康和老龄化科技应对

学科代码

未公开

基金类别

“主动健康和老龄化科技应对”重点专项

关键词

灵长类动物 ; 早衰症 ; 衰老 ; 机制研究 ; non-human primate ; progeria ; aging ; mechanism study

参与者

毛志勇;慈维敏;初群

参与机构

同济大学;中国科学院北京基因组研究所

项目标书摘要:本年度项目团队围绕项目设置的研究目标,在建立衰老研究体系,尤其是优化和开发精准基因编辑工具方面取得了一定突破。一方面,团队建立了新一代基因编辑工具脱靶检测技术,并通过对单碱基编辑工具的改造,进一步完善了现有基因编辑工具。另一方面,团队通过对食蟹猴胚胎基因编辑,初步获得F0代WRN基因缺失的猴子模型。此外,通过进一步结合人胚胎干细胞技术,团队建立了人科凯恩氏综合征干细胞研究体系以及多种衰老相关疾病模型。基于上述研究体系,团队利用新型的DNA损伤修复报告工具初步发现干细胞衰老过程中特异的DNA损伤修复调控途径;成功获得了人源端粒酶HACA调节复合物5.9 分辨率的冷冻电镜电子密度数据;初步绘制了食蟹猴动物心脏、肝脏、肌肉增龄转录组图谱和m6A表观遗传修饰图谱,并构建衰老相关的生物学数据库。在衰老及衰老相关疾病的干预方面,团队通过靶向编辑单个长寿基因产生了首例遗传增强的人类血管细胞;揭示了CBX4,YAP-FOXD1通路和miRNA合成通路关键因子DGCR8在人干细胞衰老调控及骨关节炎基因治疗中的作用及分子机制;通过对小分子化合物库的通量筛选,发现长期低剂量槲皮素处理可以延长小鼠健康寿命。项目在本执行年度在包括Nature,Science以及Cell Stem Cell 等在内著名学术期刊发表共计23篇研究论文,申请或获授权了14项中国和国际PCT专利。

Application Abstract: Aiming to study the underlying mechanism of primate aging and identify aging biomarkers,we firstly developed a method named GOTI(Genome wide off target analysis by two cell embryo injection)to detect off-target mutations caused by either CRISPR-Cas9 or base editors,the most popular gene editing tools,and we identified that cytosine base editing induced SNVs at more than 20-fold higher frequencies,requiring a solution to address its fidelity.Subsequently,by engineering deaminases,we modified the both ABE and CBE gene editing tools with a significant reduction in off-target RNA SNVs.Meantime,utilizing gene editing tools,we generated F0 generation of“Werner Syndrome”cynomolgus monkey by knock out WRN gene.We also established the human Cockayne syndrome stem cell model revealing that defects in DNA repair account for CS pathologies.Based on the above research systems for primate aging study,we carried out the following mechanism studies:delineating the DNA damage repair pathways responsible for the senescence of human adipocyte stem cells;acquisition of the crystal structure of human telomerase complex with 5.9 resolution;profiling the N6-methyladenosine(m5A)epitranome of human progeria and multi organs of aged monkeys and their control counterparts,and further established the Agingbank providing profound and accurate resources and tools for aging research.In terms of the intervention of aging and aging associated diseases,we generated the first genetically enhanced human vascular cells through targeted editing of the longevity gene FOXO3A;revealed the role of key rejuvenation factors including CBX4,YAP,FOXD1 and DGCR8 for human stem cell aging and developed novel gene therapy of the aging-related disease such as osteoarthritis;revealed that the long-term low-dose quercetin treatment prolonged the healthy life of mice.All of the above work was accomplished by the end of year 2019,with 23 SCI papers published.

项目受资助省

北京市

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  • 3. Mesenchymal stem cell therapy protects lungs from radiation-induced endothelial cell loss by restoring superoxide dismutase 1 expression.Antioxid Redox Signal 2017 Apr 10;26(11):563-582

  • 4. (2021).LossofWnt9aaggravatestherheumatoidarthritis-likesymptomsinhTNFtransgenicanimals.CellDeath&Disease12(5)

  • 5.Bariatric surgery and COVID-19 outcomes: a systematic review and meta-analysis

    • 关键词:
    • COVID-19; Bariatric surgery; Meta-analysis;CORONAVIRUS DISEASE 2019; NEWCASTLE-OTTAWA SCALE; METABOLIC SURGERY;WEIGHT-LOSS; ASSOCIATION; SEVERITY; QUALITY

    Background: Obesity and its associated complications have a negative impact on human health. Metabolic and bariatric surgery (MBS) ameliorates a series of clinical manifestations associated with obesity. However, the overall efficacy of MBS on COVID-19 outcomes remains unclear.Objectives: The objective of this article is to analyze the relationship between MBS and COVID-19 outcomes.Setting: A meta-analysis.Methods: The PubMed, Embase, Web of Science, and Cochrane Library databases were searched to retrieve the related articles from inception to December 2022. All original articles reporting MBS-confirmed SARS-CoV-2 infection were included. Outcomes including hospital admission, mortality, intensive care unit (ICU) admission, mechanical ventilation utilization, hemodialysis during admis-sion, and hospital stay were selected. Meta-analysis with fixed or random-effect models was used and reported in terms of odds ratios (ORs) or weighted mean differences (WMDs) along with their 95% confidence intervals (CIs). Heterogeneity was assessed with the I2 test. Study quality was assessed using the Newcastle-Ottawa Scale.Results: A total of 10 clinical trials involving the investigation of 150,848 patients undergoing MBS interventions were included. Patients who underwent MBS had a lower risk of hospital admission (OR: .47, 95% CI: .34-.66, I2 = 0%), mortality (OR: .43, 95% CI: .28-.65, I2 = 63.6%), ICU admis-sion (OR: .41, 95% CI: .21-.77, I2 = 0%), and mechanical ventilation (OR: .51, 95% CI: .35-.75, I2 = 56.2%) than those who did not undergo surgery, but MBS did not affect hemodialysis risk or COVID-19 infection rate. In addition, the length of hospital stay for patients with COVID-19 after MBS was significantly reduced (WMD: -1.81, 95% CI: -3.11-.52, I2 = 82.7%).Conclusions: Our findings indicate that MBS is shown to improve COVID-19 outcomes, including hospital admission, mortality, ICU admission, mechanical ventilation, and hospital stay. Patients with obesity who have undergone MBS infected with COVID-19 will have better clinical outcomes than those without MBS. (Surg Obes Relat Dis 2023;19:1058-1066.)& COPY; 2023 Published by Elsevier Inc. on behalf of American Society for Metabolic and Bariatric Surgery.

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  • 6. Posterpräsentation:Jahrestagung der Deutschen,Österreichischen und Schweizerischen Gesellschaften für Hämatologie und Medizinische Onkologie,Hamburg 2014

  • 10.Biomarkers of aging

    • 关键词:
    • aging; senescence; biomarker; clock;AGE-RELATED-CHANGES; HEMATOPOIETIC STEM-CELLS; NF-KAPPA-B; BROWNADIPOSE-TISSUE; MITOCHONDRIAL-DNA MUTATIONS; SMOOTH-MUSCLE-CELLS;INTIMA-MEDIA THICKNESS; ANTI-MULLERIAN HORMONE; GLYCATION END-PRODUCTS;FOLLICLE-STIMULATING-HORMONE

    Aging biomarkers are a combination of biological parameters to (i) assess age-related changes, (ii) track the physiological aging process, and (iii) predict the transition into a pathological status. Although a broad spectrum of aging biomarkers has been developed, their potential uses and limitations remain poorly characterized. An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research: How old are we? Why do we get old? And how can we age slower? This review aims to address this need. Here, we summarize our current knowledge of biomarkers developed for cellular, organ, and organismal levels of aging, comprising six pillars: physiological characteristics, medical imaging, histological features, cellular alterations, molecular changes, and secretory factors. To fulfill all these requisites, we propose that aging biomarkers should qualify for being specific, systemic, and clinically relevant.

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