Deconstructing aging with senolytic CAR T cells

用 senolytic CAR T 细胞解构衰老

• 批准号: 10473167
• 负责人: Corina Amor Vegas
• 金额: $ 48万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10473167
• 关键词: Advisory Committees; Affect; Aging; Area; Biological; Biology; Biology of Aging; CAR T cell therapy; Cell Aging; Cell Cycle Arrest; Cell Therapy; Cell surface; Cells; Characteristics; Chronic; Collaborations; Data; Development; Disease; Educational workshop; Environment; Enzymes; Faculty; Feedback; Foundations; Freedom; Functional disorder; Genes; Genetic Transcription; Goals; Grant; HRK gene; Health; Homeostasis; Image; Immune; Immune system; Immunologic Surveillance; Laboratories; Lead; Leadership; Learning; Longevity; Mentors; Methods; Modality; Molecular; Monitor; Organism; Pathogenesis; Pathologic; Pathology; Phenotype; Play; Positioning Attribute; Pre-Clinical Model; Proteomics; Recording of previous events; Research; Research Personnel; Resolution; Resource Sharing; Resources; Role; Schools; Scientist; Solid; Surface; TP53 gene; Therapeutic; Time; Tissues; Tumor Suppression; Tumor Suppressor Proteins; Work; Writing; age related; aged; base; biological adaptation to stress; career; career development; chimeric antigen receptor T cells; collaborative environment; cytokine; experience; flexibility; gene repression; graduate student; imaging study; immune clearance; in vivo; inflammatory milieu; innovation; insight; intravital imaging; leadership development; meetings; member; mouse model; novel; older patient; paracrine; preclinical study; professor; programs; recruit; selective expression; senescence; skills; socioeconomics; success; supportive environment; symposium; therapy design; tool; wound healing

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.

总结 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，委员会认为， 细胞衰老是生物体衰老的一个关键但知之甚少的决定因素。衰老是一种压力 反应程序，其特征在于稳定的细胞周期停滞。最初被描述为肿瘤抑制因子 它涉及肿瘤抑制因子p53和RB之间的相互作用，导致转录水平的降低。 基因抑制程序，使增殖相关基因沉默。衰老细胞除了被抑制外 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，以及促进衰老。 募集免疫细胞，其作用是清除衰老细胞并恢复组织稳态。的确， 这是在伤口愈合或肿瘤抑制的情况下发生的。然而，对于 目前尚不清楚，在某些情况下，如衰老或与年龄有关的疾病，衰老细胞积累超过 产生病理性慢性促炎环境的时间，该环境在炎症的病理生理学中起关键作用。 了以下条件我们的目标是鉴定在衰老细胞中选择性表达的细胞表面标志物， 为了更好地识别，分离和表征衰老程序， 衰老与此同时，我们将利用这些分子的选择性特征， 成像策略，以监测体内衰老细胞，以及开发能够选择性地 消除衰老细胞。我们将使用这些衰老清除CAR T细胞来功能性地询问 以及研究其在年龄相关的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 一种细胞表面分子在衰老细胞上表达，并验证了CAR T细胞的潜力 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 额外的标记物，表征衰老中衰老的分子程序并优化细胞治疗 老化条件的设计。冷泉港实验室有着悠久的历史， 早期的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 发展这个项目，并作为一名独立研究员启动我自己的研究计划。完成 拟议的工作将更好地定义衰老中的衰老状态，对衰老的生物学产生新的见解。 衰老免疫监视，并产生一种新的模式，既询问衰老和治疗年龄- 相关疾病。