Harnessing CAR T cells to deconstruct the interconnectivity among hallmarks of aging

利用 CAR T 细胞解构衰老标志之间的相互关联

• 批准号: 10722706
• 负责人: Corina Amor Vegas
• 金额: $ 53.4万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722706
• 关键词: Acceleration; Affect; Aging; Antigens; Atherosclerosis; Biology; Biology of Aging; Breeding; Categories; Cell Aging; Cell Therapy; Cells; Chemicals; Complex; Consumption; Dasatinib; Data; Development; Disease; Dose; Engineering; Epigenetic Process; Genomic Instability; Goals; Individual; Light; Longevity; Mitochondria; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Pathology; Phenotype; Physiological; Process; Research; Resources; Safety; Specificity; Surface; Technology; Therapeutic; Therapeutic Studies; Time; Tissues; Toxic effect; Use Effectiveness; Work; age related; aged; antagonist; cellular engineering; chimeric antigen receptor T cells; cost; design; detection of nutrient; exhaustion; experimental study; flexibility; gastrointestinal system; healthspan; improved; insight; intercellular communication; irradiation; mitochondrial dysfunction; mouse model; novel therapeutics; pathological aging; programs; proteostasis; response; senescence; small molecule; stem cells; telomere; therapeutic evaluation; tool

SUMMARY To date nine hallmarks of the aging process have been described, which can be grouped into three major categories: primary hallmarks or cause of damage (genomic instability, telomere attrition, epigenetic alterations and loss of proteostasis), antagonist hallmarks or responses to damage (cellular senescence, mitochondrial dysfunction and deregulated nutrient sensing) and integrative hallmarks or manifestations of the aging phenotype (stem cell exhaustion and altered intercellular communication). Despite intensive research on each individual hallmark, little is known about their interconnectivity and the hierarchies governing those interactions. A limiting factor in these studies is the time and resources needed for developing, breeding and aging mouse models that would allow to untangle the interactions as well as the lack of highly selective small molecules that would enable somatic approaches. In this regard, our recent work showed for the first time the feasibility of employing cellular therapy to eliminate cells that have entered a specific cellular program such as cellular senescence. In a proof- of-concept study we identified uPAR as a surface molecule upregulated in cellular senescence and developed CAR T cells able to eliminate senescent cells with high potency and specificity. CAR T cells have the advantage that they can be administered somatically and are highly effective at exclusively targeting cells expressing a specific antigen. In addition, they offer the possibility of spatial and temporal control making them highly versatile tools. Herein we leverage our team’s expertise in senescence biology and cell engineering technology to shed light into the interactions among the hallmarks of aging. Our goals are to characterize in depth the impact of senolytic CAR T cells on the antagonistic and integrative hallmarks of aging; develop tissue specific senolytic CAR T cells that would allow us to untangle hierarchies among the hallmarks across physiological lifespan and study the therapeutic potential of modulating the interactions for the treatment of age-related pathologies. Preliminary data strongly supports the feasibility of the proposed work: we have successfully and safely employed senolytic CAR T cells in naturally aged mice and showed their high potency at eliminating target positive cells in the tissues over long periods of time. Importantly, treatment with senolytic CAR T cells results in significant improvements in healthspan. In our application, we continue to characterize in a systematic way the effects across hallmarks and harness the flexibility of cellular therapy to untangle the hierarchies governing the interactions. Overall, we expect our studies will lead to versatile tools to interrogate aging biology as well as to the development of new therapies for a range of age-related pathologies.

概括 迄今为止，已经描述了衰老过程的九个特征，可分为三个主要特征 类别：主要标志或损伤原因（基因组不稳定、端粒磨损、表观遗传改变 和蛋白质稳态丧失）、拮抗剂标志或对损伤的反应（细胞衰老、线粒体 功能障碍和营养感应失调）以及衰老表型的综合标志或表现 （干细胞衰竭和细胞间通讯改变）尽管对每个个体进行了深入的研究。 标志性的是，人们对它们的互连性以及管理这些交互的层次结构知之甚少。 这些研究的因素是开发、繁殖和衰老小鼠模型所需的时间和资源， 将能够解开相互作用以及缺乏高度选择性的小分子，这将使 在这方面，我们最近的工作首次证明了采用细胞方法的可行性。 消除已进入特定细胞程序（例如细胞衰老）的细胞的疗法。 在概念研究中，我们确定了 uPAR 是一种在细胞衰老过程中上调的表面分子，并开发了 CAR T细胞能够高效、特异性地消除衰老细胞。 它们可以通过体细胞给药，并且在专门针对表达 a 的细胞方面非常有效 此外，它们提供了空间和时间控制的可能性，使它们具有高度的通用性。 在这里，我们利用我们团队在衰老生物学和细胞工程技术方面的专业知识来摆脱。 我们的目标是深入描述衰老特征之间的相互作用。 senolytic CAR T 细胞针对衰老的拮抗和综合特征开发出组织特异性的 senolytic CAR T 细胞将使我们能够理清生理寿命和生命周期特征之间的层次结构 研究调节相互作用治疗年龄相关病理的治疗潜力。 初步数据有力地支持了拟议工作的可行性：我们已经成功且安全地 在自然衰老的小鼠中使用 senolytic CAR T 细胞，并显示出其消除靶标的高效力 重要的是，使用 senolytic CAR T 细胞治疗会导致组织中的细胞长期呈阳性。 在我们的应用中，我们继续以系统的方式描述健康寿命的显着改善。 跨标志的影响，并利用细胞疗法的灵活性来理清管理的层次结构 总的来说，我们预计我们的研究将带来多种工具来探究衰老生物学以及研究衰老生物学。 开发针对一系列与年龄相关的疾病的新疗法。