Deconstructing aging with senolytic CAR T cells

用 senolytic CAR T 细胞解构衰老

基本信息

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
项目类别：
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

项目摘要

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.

概括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。对此，细胞衰老是机体衰老的一个关键但人们知之甚少的决定因素。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。最初被描述为肿瘤抑制因子机制，它涉及肿瘤抑制因子 p53 和 RB 之间的相互作用，导致转录基因抑制程序，使增殖相关基因沉默。除了被捕之外，衰老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以及招募免疫细胞，其作用是清除衰老细胞并恢复组织稳态。的确，这就是在伤口愈合或肿瘤抑制的情况下发生的情况。然而，对于机制目前尚不清楚，在某些情况下，例如衰老或与年龄相关的疾病，衰老细胞会积累超过时间产生病理性慢性促炎环境，在病理生理学中发挥关键作用这些条件。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衰老细胞的目的是为了更好地识别、分离和表征衰老程序老化。与此同时，我们将利用这些分子的选择性特征，旨在开发更好的监测体内衰老细胞以及开发能够选择性地进行 CAR T 细胞的成像策略消除衰老中的衰老细胞。我们将使用这些 senolytic CAR T 细胞来进行功能性询问体内衰老生物学以及研究其在年龄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表达的一种细胞表面分子，验证了 CAR T 细胞的潜力将其作为有效且安全的抗衰老药物。在我们的应用程序中，我们继续识别和验证额外的标记物，表征衰老过程中衰老的分子程序并优化细胞治疗针对老化条件的设计。冷泉港实验室有着悠久的成功培育历史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作为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方式来询问衰老和治疗年龄相关疾病。