Deconstructing aging with senolytic CAR T cells

摘要 更好地了解衰老生物学是一个紧迫的健康和社会经济问题。在这方面， 细胞衰老是生物体衰老的关键，但人们对此知之甚少。衰老是一种压力 以稳定的细胞周期停滞为特征的反应程序。最初被描述为一种肿瘤抑制因子 机制，它涉及肿瘤抑制基因P53和Rb之间的相互作用，导致转录 抑制增殖相关基因的基因抑制程序。在它们被逮捕之后，衰老的细胞 分泌由细胞因子和基质组成的衰老相关分泌表型(SASP) 重塑酶。SASP有助于诱导旁分泌衰老，并有助于 免疫细胞的招募，其作用是清除衰老的细胞，恢复组织的动态平衡。的确， 这就是在伤口愈合或肿瘤抑制的背景下发生的事情。然而，对于 尚不清楚，在某些情况下，如衰老或与年龄相关的疾病，衰老细胞积累超过 产生病理性慢性促炎环境的时间在心力衰竭的病理生理学中起关键作用 这些条件。我们的目标是确定在衰老过程中选择性表达的细胞表面标志 为了更好地识别、分离和表征衰老过程中的细胞 衰老。同时，我们将利用这些分子的选择性特征，以期发展得更好。 监测体内衰老细胞以及发展能够选择性地 消除衰老中的细胞衰老。我们将使用这些分解感觉神经的CAR T细胞来功能性地询问 体内衰老生物学及其在老年相关临床前模型中的治疗潜力 疾病。初步数据有力地支持了拟议工作的可行性：我们已经确定 衰老细胞上一种细胞表面分子的表达及CAR T细胞潜能的验证 将其作为有效和安全的抗衰老药物。在我们的应用程序中，我们继续识别和验证 其他标记物，表征衰老的分子程序并优化细胞治疗 针对老化条件的设计。冷泉港实验室培育成功的历史源远流长 早期科学家通过他们的独立研究员计划。这种高度支持的环境是一个理想的利基市场 开发这个项目，并以独立研究员的身份启动自己的研究计划。已完成的 拟议的工作将更好地定义衰老状态，对 衰老免疫监测并产生一种既能询问衰老又能治疗衰老的新模式- 相关疾病。

SUMMARY Gaining a better understanding of aging biology is a pressing health and socioeconomic issue. In this regard, cellular senescence is a key, but poorly understood determinant of organismal aging. Senescence is a stress response program characterized by stable cell cycle arrest. Initially described as a tumor suppressor mechanism, it involves the interplay between the tumor suppressors p53 and RB leading to a transcriptional program of gene repression that silences proliferation associated genes. Beyond their arrest, senescent cells secrete the senescence associated secretory phenotype (SASP) composed of cytokines and matrix remodeling enzymes. The SASP contributes to the induction of paracrine senescence as well as to the recruitment of immune cells, whose role is to clear the senescent cells and restore tissue homeostasis. Indeed, this is what happens in the context of wound healing or tumor suppression. However, for mechanisms that remain unclear, in certain settings such as aging or age-related diseases, senescent cells accumulate over time generating a pathological chronic pro-inflammatory milieu that plays a key role in the pathophysiology of these conditions. Our goals are to identify cell surface markers that are selectively expressed in senescent cells in aging for the purpose of better identifying, isolating and characterizing the senescence program in aging. In parallel, we will exploit the selective features of these molecules with the aim of developing better imaging strategies to monitor senescent cells in vivo as well as of developing CAR T cells able to selectively eliminate senescent cells in aging. We will use these senolytic CAR T cells to functionally interrogate senescence biology in vivo as well as to study their therapeutic potential in preclinical models of age-related diseases. Preliminary data strongly supports the feasibility of the proposed work: we have already identified one cell surface molecule expressed on senescent cells in aging and validated the potential of CAR T cells targeting it as effective and safe senolytics in aging. In our application, we continue to identify and validate additional markers, characterize the molecular program of senescence in aging and optimize cellular therapy designs for aging conditions. Cold Spring Harbor Laboratory has a longstanding history of nurturing successful early scientist through their Independent Fellows program. This highly supportive environment is an ideal niche to develop this project and launch my own research program as an Independent Fellow. Completion of the proposed work will better define the senescence state in aging, produce new insights into the biology of senescence immune surveillance and generate a new modality to both interrogate senescence and treat age- related diseases.