In Vitro and In Vivo Biology of Telomere Stress Induced Senescence

端粒应激诱导衰老的体外和体内生物学

基本信息

项目摘要

PROJECT SUMMARY Senescent cells have been implicated as drivers of aging and age-associated diseases. Senescent cells have sustained some form of stress that causes irreversible cell-cycle arrest, and these cells avoid apoptosis. These cells have a hyper-metabolic phenotype and secrete cytokines and chemokines resulting in the senescence associated secretory phenotype (SASP). The SASP contains multiple inflammatory components which promotes tissue dysfunction. These observations have been the impetus to develop senolytic drugs. These drugs are designed to cause the selective apoptosis of senescent cells and several senolytics have already entered clinical trials for potential use in idiopathic pulmonary fibrosis, osteoarthritis, chronic diabetes, etc. Many of these senolytic drugs have been developed via a candidate approach where drugs that were initially developed for the treatment of cancer are repurposed for the clearance of senescent cells. These drugs, unfortunately, have both on-target and off-target dose-limiting side effects such as thrombocytopenia and trabecular bone loss. Therefore, there is a need to develop senolytic drugs that target a specific underlying vulnerability of senescent cells without affecting healthy cells. In this project, we have performed an unbiased CRISPR-based, whole genome synthetic lethality screen to identify genes when knocked out, are lethal in the setting of a cell that has undergone telomere-induced senescence yet are well-tolerated when knockout in the context of a healthy, non-senescent cell. Through this screen, we identified that genetic alterations in ER stress pathways are specific vulnerabilities of senescent cells. Specifically, the targets ER-resident proteins, PARP16 and BIP, which were identified in the CRISPR screen, modulate ER stress pathways. Therefore, we hypothesize that due to their high secretory burden, senescent cells are particularly vulnerable to alterations in ER stress pathways. We propose to investigate the following: (1) Identify and characterize the set of genes which when knocked out in senescent cells cause the specific death of these cells without affecting the function of healthy cells; (2) Understand whether senescent cells that undergo telomere induced senescence have higher levels of ER stress and whether alterations in these pathways affect the viability of senescent cells and the production of SASP components; (3) Understand whether telomere-induced senescence affects the function of post- mitotic cells such as cardiomyocytes and in turn, whether cardiomyocyte senescence affect heart function. This proposal will therefore lead to a better understanding of the unique molecular vulnerabilities of senescent cells and clarify the molecular underpinnings of how cells maintain a state of senescence. Successful completion of this proposal will provide a foundation for the development of senolytics to treat a variety of aging-associated diseases. Finally, this proposal will provide me with an outstanding platform to build my basic science and clinical thinking skills so that I can pursue a career as a physician scientist.
项目概要 衰老细胞被认为是衰老和与年龄相关的疾病的驱动因素。衰老细胞有 持续某种形式的压力会导致不可逆的细胞周期停滞,并且这些细胞避免凋亡。这些 细胞具有高代谢表型并分泌细胞因子和趋化因子,导致衰老 相关分泌表型(SASP)。 SASP 含有多种炎症成分, 促进组织功能障碍。这些观察结果推动了抗衰老药物的开发。这些 药物旨在引起衰老细胞的选择性凋亡,并且几种 senolytics 已经 进入临床试验,潜在用于特发性肺纤维化、骨关节炎、慢性糖尿病等。 许多这些 senolytic 药物是通过候选方法开发的,其中最初的药物 为治疗癌症而开发的药物被重新用于清除衰老细胞。这些药物, 不幸的是,具有靶向和脱靶剂量限制副作用,例如血小板减少症和 小梁骨丢失。因此,需要开发针对特定潜在因素的抗衰老药物。 衰老细胞的脆弱性而不影响健康细胞。在这个项目中,我们进行了公正的 基于 CRISPR 的全基因组合成致死性筛选,用于识别基因被敲除时是否具有致命性 细胞经历了端粒诱导的衰老,但在基因敲除后仍具有良好的耐受性。 健康、非衰老细胞的背景。通过这个筛选,我们发现 ER 应激的基因改变 途径是衰老细胞的特定脆弱性。具体来说,目标是内质网驻留蛋白 PARP16 CRISPR 筛选中发现的 BIP 和 BIP 可以调节 ER 应激途径。因此,我们 假设由于衰老细胞的高分泌负担,它们特别容易受到 ER 应激途径。 我们建议研究以下内容:(1)识别并表征一组基因,当 衰老细胞中的敲除会导致这些细胞的特异性死亡,而不影响健康细胞的功能 细胞; (2)了解经历端粒诱导衰老的衰老细胞是否具有更高水平的 内质网应激以及这些途径的改变是否会影响衰老细胞的活力和生产 SASP 组件; (3) 了解端粒诱导的衰老是否影响端粒后的功能 有丝分裂细胞,例如心肌细胞,进而了解心肌细胞衰老是否影响心脏功能。 因此,该提案将有助于更好地了解 衰老细胞并阐明细胞如何维持衰老状态的分子基础。 该提案的成功完成将为开发治疗老年痴呆症的 senolytics 奠定基础。 各种与衰老相关的疾病。最后,这个提案将为我提供一个出色的平台来构建 我的基础科学和临床思维技能使我能够从事医学科学家的职业。

项目成果

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