Identification of Splicing-Related Aging Biomarkers

剪接相关衰老生物标志物的鉴定

• 批准号: 8821400
• 负责人: KAN CAO
• 金额: $ 22.2万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821400
• 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（由适用提供）：细胞衰老是探索组织衰老潜在的分子机制的强大体外模型。一个流行的假设是，当端粒缩短到低于临界点以下时，它充当有丝分裂时钟，决定了从细胞周期中永久退出。除了端粒缩短外，某些肿瘤基因或环境刺激（例如γ-辐射）可以过早触发细胞感应。还据报道，由于外显子11中从头突变导致层粘连蛋白A基因（LMNA）的异常剪接导致Hutchinson-Gilford Formia综合征（HGPS）的患者导致过早的细胞感染和加速衰老。有趣的是，HGP（称为“孕激素”）在健康个体的细胞和组织中积聚了lamin a的少量异常剪接产物，这与年龄的关系表明，mRNA剪接的变化不一定与突变有关，并且也可能受到年龄相关因素的影响。与这种思维线一致，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，也被剪接在正常的感觉细胞中。在与衰老有关的神经退行性疾病中，例如阿尔茨海默氏症，帕金森氏症和陶氏病，这也涉及涉及MRNA前剪接的畸变。基于上述发现，我们假设在细胞感应期间替代剪接存在宽度变化。这些与感应相关的同工型中的一些可能是感应细胞独有的，对于细胞建立感应态在功能上很重要，可以进一步发展为新型的衰老生物标志物。为了解决这一假设，我们将进行一系列研究，包括使用RNA-Seq（AIM1）鉴定培养的感官细胞的剪接变化，以表征这些在体外和体内这些感应相关的同工型，并将其发展为衰老的生物标志物（AIM2）。