Identification of Splicing-Related Aging Biomarkers

剪接相关衰老生物标志物的鉴定

• 批准号: 8929113
• 负责人: KAN CAO
• 金额: $ 17.85万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8929113
• 关键词: Address; Age; Aging; Alternative Splicing; Alzheimer' s Disease; Antibodies; Appearance; Biological Markers; Cell Adhesion Molecules; Cell Aging; Cell Cycle; Cells; Custom; Data Set; Development; Disease; Exons; Fibroblasts; Fibronectins; Functional disorder; Genes; Goals; Health; Heterochromatin; Heterogeneity; Human; In Vitro; Individual; Intermediate Filament Proteins; Interphase Cell; Investigation; Lamin Type A; Lead; Malignant Neoplasms; Messenger RNA; Mitotic; Molecular; Mus; Mutation; Names; Neurodegenerative Disorders; Oncogenes; Ontology; Parkinson Disease; Pathway interactions; Patients; Physiological; Preclinical Drug Evaluation; Premature aging syndrome; Primates; Progeria; Proliferating; Protein Isoforms; Proteins; Public Health; RNA; RNA Splicing; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Sequence Analysis; Series; Signal Pathway; Sirolimus; Skin; Small Interfering RNA; Stimulus; Stress; Syndrome; Tauopathies; Telomere Shortening; Thinking; Tissue Sample; Tissues; Tumor Suppression; Vimentin; age related; aged; base; beta-Galactosidase; comparative; in vitro Model; in vivo; irradiation; loss of function; mRNA Precursor; novel; oxidation; premature; research study; senescence; telomere; tool; transcriptome sequencing

DESCRIPTION (provided by applicant): Cellular aging is a powerful in vitro model for exploring molecular mechanisms underlying organismal aging. A popular hypothesis is that, when the telomeres shorten to below a critical point, it acts as a mitotic clock dictating the permanent exit from the cell cycle. Besides telomere shortening, cellular senescence can be triggered prematurely by certain oncogenes or environmental stimuli, such as γ-irradiation. It has also been reported that an aberrant splicing of the pre-mRNA of the lamin A gene (LMNA), due to a de novo mutation in the exon 11, leads to premature cellular senescence and accelerated aging in patients with Hutchinson-Gilford progeria syndrome (HGPS). Interestingly, a small amount of the aberrant splicing product of lamin A in HGPS (named "progerin") accumulates in the cells and tissues of healthy individuals as a function of age, suggesting that alterations in mRNA splicing are not necessarily associated with mutations and may also be influenced by age-related factors. Consistent with this line of thinking, a few other genes, including a cell adhesion molecule fibronectin and an intermediate filament protein vimentin, are alternatively spliced in normal senescent cells. This idea is also exemplified in aging-related neurodegenerative diseases, such as Alzheimer's, Parkinson's diseases and tauopathies, all involving aberrations in pre-mRNAs splicing. Based on the above findings, we hypothesize that there are widespread changes in alternative splicing during cellular senescence. Some of these senescence-related isoforms may be unique to senescent cells and functionally important for cells to establishing senescence state, which can be further developed into novel biomarkers for aging. To address this hypothesis, we will conduct a series of investigations including identifying splicing changes in cultured senescent cells using RNA-seq (Aim1), characterizing these senescence-associated isoforms in vitro and in vivo to develop them into aging biomarkers (Aim2).

描述（由申请人提供）：细胞衰老是探索生物衰老分子机制的强大体外模型，一个流行的假设是，当端粒缩短到临界点以下时，它充当有丝分裂时钟，指示永久退出。除了端粒缩短之外，某些致癌基因或环境刺激（例如 γ 辐射）也会导致细胞过早衰老。由于外显子 11 的从头突变，核纤层蛋白 A 基因 (LMNA) 前体 mRNA 的剪接会导致哈钦森-吉尔福德早衰综合征 (HGPS) 患者的细胞过早衰老和加速衰老。 HGPS 中核纤层蛋白 A 的剪接产物（称为“早老素”）在健康个体的细胞和组织中随着年龄的增长而积累，这表明 mRNA 的变化剪接不一定与突变有关，也可能受到年龄相关因素的影响，与这种思路一致的是，其他一些基因，包括细胞粘附分子纤连蛋白和中间丝蛋白波形蛋白，在正常情况下是交替剪接的。这一想法在与衰老相关的神经退行性疾病中也得到了体现，例如阿尔茨海默病、帕金森病和 tau 病，所有这些都与前 mRNA 的畸变有关。基于上述发现，我们发现细胞衰老过程中选择性剪接发生了广泛的变化，其中一些与衰老相关的亚型可能是衰老细胞所独有的，并且对于细胞建立衰老状态具有重要的功能，可以进一步开发。为了解决这一假设，我们将进行一系列研究，包括识别。 使用 RNA-seq 检测培养的衰老细胞中的剪接变化 (Aim1)，在体外和体内表征这些衰老相关亚型，将其开发为衰老生物标志物 (Aim2)。

项目成果

Transient induction of telomerase expression mediates senescence and reduces tumorigenesis in primary fibroblasts.

端粒酶表达的瞬时诱导介导衰老并减少原代成纤维细胞的肿瘤发生。

• 发表时间: 2019
• 影响因子: 11.1
• 作者: Sun, Linlin;Chiang, Jeffrey Y;Choi, Ji Young;Xiong, Zheng;Mao, Xiaojing;Collins, Francis S;Hodes, Richard J;Cao, Kan
• 通讯作者: Cao, Kan

Comparing lamin proteins post-translational relative stability using a 2A peptide-based system reveals elevated resistance of progerin to cellular degradation.

使用基于 2A 肽的系统比较核纤层蛋白翻译后的相对稳定性，揭示了早老素对细胞降解的抵抗力增强。

• 发表时间: 2016-11
• 作者: Wu, Di;Yates, Phillip A;Zhang, Haoyue;Cao, Kan
• 通讯作者: Cao, Kan

Anti-Aging Potentials of Methylene Blue for Human Skin Longevity.

亚甲基蓝对人类皮肤长寿的抗衰老潜力。

• 发表时间: 2017
• 影响因子: 4.6
• 作者: Xiong, Zheng;O'Donovan, Mike;Sun, Linlin;Choi, Ji Young;Ren, Margaret;Cao, Kan
• 通讯作者: Cao, Kan

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria.

亚甲蓝可减轻早衰症的核和线粒体异常。

• 发表时间: 2016-04
• 影响因子: 7.8
• 作者: Xiong, Zheng;Choi, Ji Young;Wang, Kun;Zhang, Haoyue;Tariq, Zeshan;Wu, Di;Ko, Eunae;LaDana, Christina;Sesaki, Hiromi;Cao, Kan
• 通讯作者: Cao, Kan

Comprehensive map of age-associated splicing changes across human tissues and their contributions to age-associated diseases.

人体组织中与年龄相关的剪接变化及其对与年龄相关疾病的贡献的综合图谱。

• 发表时间: 2018-07-19
• 影响因子: 4.6
• 作者: Wang, Kun;Wu, Di;Zhang, Haoyue;Das, Avinash;Basu, Mahashweta;Malin, Justin;Cao, Kan;Hannenhalli, Sridhar
• 通讯作者: Hannenhalli, Sridhar