Restoring the functionality of the old immune system by rejuvenation of aged hematopoietic stem cells

通过使老化的造血干细胞恢复活力来恢复旧免疫系统的功能

• 批准号: 436784456
• 负责人: Professor Dr. Hartmut Geiger
• 金额: --
• 依托单位: Institut für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/436784456?language=en
• 关键词: Restoring; functionality; old; immune; system

Restoring the functionality of the old immune system by rejuvenation of aged hematopoietic stem cells. Aging is associated with a variety of changes in the immune system summarized as aging-associated immune remodeling (AAIR). AAIR is thought to be a major cause of the reduced function of the immune system in the elderly. While the role of thymic involution has been studied and discussed as an important contributing factor to AAIR, there is only limited information available on the extent to which aging of hematopoietic stem cells (HSCs), from which lymphocytes are ultimately derived, contributes to AAIR. Aging of HSCs is in part driven by elevated activity of the small RhoGTPase Cdc42. In vitro treatment of aged HSCs with the Cdc42 activity inhibitor CASIN resulted in long-term epigenetic and morphological changes that may drive the reconstitution of a youthful and immune-competent immune system. The proposal aims to elucidate (i) the development of complex immune systems stemming from young or aged HSCs, also under the influence of an aged bone marrow niche.(ii) molecular and mechanistic links between HSC aging and the phenotypic and functional changes in the aged immune system (iii) in vitro rejuvenation of aged HSCs with the pharmacological compound CASIN. Of particular interest are CASIN-induced molecular signatures in aged HSCs and the corresponding HSC-derived immune cells that shift their ´aged´ differentiation program towards a youthful immune system capable of mounting strong responses to vaccination. To study the generation of a complex immune system from HSCs, we use a novel HSC-transplantation model in T- and B-cell deficient young RAG1-/- hosts. We will transplant young, aged or CASIN treated aged HSCs into RAG1-/- hosts to analyze distinct T-cell subsets. We will determine their transcriptome, their epigenetic changes as well as changes in their function. This model allows us to directly characterize the selective repopulation of T-cell subsets developing from donor HSCs under well-defined conditions and also to evaluate the functiona of the reconstituting immune system in vaccination studies (e.g., Protein-based vaccination). In a final set of experiment, we will investigate in as much aging of the stem cell niche also contributes to AAIR, as aging of the niche also influences aging of HSCs. In summary, these studies may help to design specific protocols that attenuate or even revert AAIR by rejuvenation of aged HSCs.

通过再生老化的造血干细胞来恢复旧免疫系统的功能。衰老与免疫系统的各种变化有关，概括为衰老相关免疫重塑（AAIR）。AAIR被认为是老年人免疫系统功能下降的主要原因。虽然胸腺退化的作用已被研究和讨论作为一个重要的促成因素AAIR，只有有限的信息可在何种程度上的造血干细胞（HSC），淋巴细胞的最终来源，有助于AAIR的老化。HSC的老化部分是由小RhoGTdR Cdc 42的活性升高驱动的。用Cdc 42活性抑制剂卡辛体外治疗老年HSC导致长期的表观遗传和形态学变化，这可能会推动年轻和免疫能力强的免疫系统的重建。该建议旨在阐明（i） 源自年轻或年老HSC的复杂免疫系统的发育，也受到年老骨髓生态位的影响。（二） HSC老化与老年免疫系统表型和功能变化之间的分子和机制联系（iii） 用药理化合物卡辛体外再生老化的HSC。特别令人感兴趣的是CASIN诱导的老年HSC和相应的HSC衍生免疫细胞的分子特征，这些细胞将其“老年”分化程序转向能够对疫苗接种产生强烈反应的年轻免疫系统。为了研究从HSC产生复杂的免疫系统，我们在T细胞和B细胞缺陷的年轻RAG 1-/-宿主中使用了一种新的HSC移植模型。我们将移植年轻的、老年的或卡辛处理的老年HSC到RAG 1-/-宿主中以分析不同的T细胞亚群。我们将确定它们的转录组、表观遗传变化以及功能变化。该模型使我们能够直接表征在明确定义的条件下从供体HSC发育的T细胞亚群的选择性再增殖，并且还可以评估疫苗接种研究中重建免疫系统的功能（例如，基于蛋白质的疫苗）。在最后一组实验中，我们将研究干细胞龛的老化也有助于AAIR，因为龛的老化也影响HSC的老化。总之，这些研究可能有助于设计特定的协议，衰减甚至逆转AAIR的老化HSC的复壮。