Investigating Cellular Senescence at the Single Cell Level

在单细胞水平上研究细胞衰老

• 批准号: 10606940
• 负责人: Rachel Cohn
• 金额: $ 4.32万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2027-06-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606940
• 关键词: Adipose tissue; Affect; Age; Aging; Biological Models; Cell Aging; Cell Nucleus; Cells; Chronic Disease; Clinical; Communication; Computer Analysis; Dasatinib; Data; Data Set; Development; Disease; Dissociation; Drug Design; Elderly; Environment; Fatty acid glycerol esters; Fellowship; Funding; Future; Gene Expression Profiling; Genetic; Genetic Markers; Goals; Growth; Health; Heterogeneity; Human; In Vitro; Individual; Inflammatory; Institution; Intervention; Investigation; Knowledge; Learning; Longevity; Mentorship; Methods; Modeling; Mus; Nuclear; Nuclear RNA; Outcome; Pathologic; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Physicians; Population; Process; Protocols documentation; Quality of life; Quercetin; RLK5-associated protein phosphatase; Reporting; Research; Risk Factors; Scientist; Techniques; The Jackson Laboratory; Tissue-Specific Gene Expression; Tissues; Training; Transgenic Mice; Validation; Work; Writing; age related; aged; career; cell growth; cell type; cost; cytokine; design; efficacious treatment; human old age (65+); human tissue; improved; in vivo; molecular marker; mouse model; novel; novel marker; oncoprotein p21; pharmacologic; pre-clinical; precision medicine; senescence; side effect; single nucleus RNA-sequencing; skills; therapy design; tissue mapping; training opportunity; transcriptome; transcriptome sequencing; transcriptomics

Project Summary/Abstract Aging is a key risk factor for chronic disease development which can affect lifespan and quality of life. Cellular senescence has emerged as a potential target to slow down the aging process. Senescent cells are in a state of proliferative arrest and are highly associated with aging and pathological conditions. They accumulate in multiple tissues and secrete pro-inflammatory cytokines and other kinds of molecules that damage surrounding tissues. The markers p16 and p21 (cyclin dependent kinase inhibitors) are commonly used to identify senescent cells, but emerging evidence has shown that these markers are not entirely sensitive or specific markers for senescence. There is currently a lack of understanding of the exact genetic markers that define senescent cells especially on the single cell level. With studies showing that senescent cell clearance can alleviate various diseases associated with aging it is vital to achieve a greater understanding of senescent cell markers so that precision medicine treatments can be designed to more effectively eliminate senescent cells. In this proposal we aim to examine the transcriptome of senescent cells on the single cell level both with aging and senolytic treatment in human adipose tissues. Senescent cells have been demonstrated to accumulate in adipose tissue with aging and chronic disease and with the vast array of cell types present in adipose tissue it makes an excellent model to study specific cell types and markers associated with senescence. Aim 1 will explore the transcriptome of naturally occurring senescent cell populations in adipose tissue with aging. We will use single nucleus RNA sequencing to capture cell types sensitive to typical single cell dissociation methods and compare the transcriptome differences between cells in aged vs. young tissues. We hypothesize that adipose tissue from older donors will contain more senescent cells and that several novel genetic markers will be identified in these cells. Aim 2 will look at the effects of senolytic treatment on human adipose tissue on the single cell level. Senolytics are drugs that are designed to specifically eliminate senescent cells but we do not know the precise cell types targeted by senolytics. We will use single nucleus RNA sequencing to uncover the transcriptome changes that occur with senescent cell elimination and learn what cell types are removed with senolytic treatment. This project will help advance the field achieving a greater understanding of senescent cell populations in adipose tissue and the markers that define them, which is essential to understanding and potentially treating numerous diseases. Through this fellowship my training will include developing my skills in genetics, aging, computational analysis, communication, presentation, networking, scientific writing, clinical knowledge and mentorship. This training will occur in the environment of UCONN Health as well as the Jackson Laboratory and other research institutions. This work will allow me to take advantage of training opportunities and mentorship to advance my career as a future physician-scientist.

项目总结/摘要 衰老是慢性疾病发展的关键风险因素，可影响寿命和生活质量。蜂窝 衰老已经成为减缓衰老过程的潜在目标。衰老细胞处于一种 增殖停滞，并且与衰老和病理状况高度相关。它们以多种形式积累 并分泌促炎细胞因子和其他类型的分子，破坏周围组织。 标记物p16和p21（细胞周期蛋白依赖性激酶抑制剂）通常用于鉴定衰老细胞， 但新出现的证据表明，这些标志物并不是完全敏感或特异的标志物， 衰老目前对定义衰老细胞的确切遗传标记缺乏了解 特别是在单细胞水平上。研究表明，衰老细胞清除可以减轻各种 与衰老相关的疾病，重要的是要更好地了解衰老细胞标志物， 精确的药物治疗可以被设计成更有效地消除衰老细胞。本提案中 我们的目标是在单细胞水平上研究衰老细胞的转录组， 人脂肪组织中的衰老清除治疗。衰老细胞已被证明积累在 脂肪组织与衰老和慢性疾病的关系以及脂肪组织中存在的大量细胞类型， 这是研究特定细胞类型和与衰老相关的标记物的极好模型。目标1将 探索脂肪组织中自然发生的衰老细胞群体的转录组。 我们将使用单核RNA测序来捕获对典型的单细胞解离敏感的细胞类型 方法，并比较老年与年轻组织中细胞之间的转录组差异。我们假设 老年捐赠者的脂肪组织将含有更多的衰老细胞， 将在这些细胞中被识别。目标2将着眼于衰老清除治疗对人体脂肪组织的影响 在单细胞水平上。Senolytics是专门用于消除衰老细胞的药物，但我们 不知道senolytics针对的确切细胞类型。我们将使用单核RNA测序来揭示 转录组的变化，发生与衰老细胞消除，并了解什么类型的细胞被删除， 衰老清除治疗这个项目将有助于推进该领域实现更好地了解衰老细胞 脂肪组织中的细胞群和定义它们的标志物，这对于理解和 可能治疗多种疾病。通过这个奖学金，我的培训将包括发展我的技能， 遗传学，老龄化，计算分析，通信，演示文稿，网络，科学写作，临床 知识和指导。这种培训将发生在康州大学健康以及杰克逊的环境 实验室和其他研究机构。这项工作将使我能够利用培训机会 和导师来推动我未来的医学科学家的职业生涯。