New Generation Blood Exchange Devices for Enhancing Tissue Regeneration and Health

用于增强组织再生和健康的新一代血液交换装置

• 批准号: 9906269
• 负责人: Kiana Aran
• 金额: $ 38.54万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-21 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906269
• 关键词: Age; Anastomosis - action; Animal Experimentation; Animals; Attenuated; Autoimmune Diseases; Back; Biological Assay; Blood; Blood Circulation; Blood Component Removal; Brain; Brain Diseases; Cell Separation; Cells; Cognition; Degenerative Disorder; Devices; Disease; Dose; Endocrine; Engineering; Environment; Excision; FDA approved; Fetal Erythroblastosis; Generations; Germ Layers; Goals; Health; Hippocampus (Brain); Human; IL6 gene; Inflammation; Inflammatory; Joints; Learning; Leukocytes; Liver; Maintenance; Mammals; Measures; Modality; Mus; Muscle; Natural regeneration; Operative Surgical Procedures; Organ; Outcome; Parabiosis; Pathology; Performance; Plasma; Procedures; Production; Proteins; Publishing; Sickle Cell Anemia; System; TNF gene; Therapeutic; Tissues; Transfusion; Work; aged; cell age; combat; cytokine; improved; in vivo; inhibitor/antagonist; myogenesis; neurogenesis; next generation; repaired; tissue regeneration

Exchange transfusion (apheresis) is a routine strategy for the management of several diseases, such as sickle cell disease, hemolytic disease of newborns, autoimmune disorders, etc. Interestingly, the body of published work on heterochronic parabiosis, the surgical joining of two animals of different ages, and more recently, our study on heterochronic blood exchange, suggest that blood apheresis can be repositioned and used as a new modality: restoring the circulatory environment of aged mammals back to a productive, young, composition, may help to rapidly and broadly enhance the maintenance and repair of multiple organs, combatting a number of degenerative diseases of brain, muscle, liver, etc. and inflammatory disorders. In contrast to the permanent anastomosis of parabiosis, in our small animal blood exchange system animals are connected and disconnected at will, removing the influence of shared organs, adaptation to being joined, etc. Unlike parabiosis, where joint circulation is stochastically established in ~7-10 days, our procedure is less invasive and accurately controlled, the exchange volumes are easily programmed and measured; and the onset and duration of the effects can be accurately and with ease interrogated. The cells versus plasma heterochronicity can be studied and immuno-affinity modules enable removal of specific inhibitory molecules from the old circulation prior to return of such “rejuvenated” blood into the old animal; as well as a screen for candidate systemic proteins, removal of which from young circulation inhibits tissue maintenance and repair. We will (1) determine the onset and duration of the effects of heterochronic blood apheresis on health and maintenance of muscle, liver and brain, animal performance (strength and cognition), and systemic cytokine profile, also defining the minimal functional dose of exchanged blood that significantly influence these parameters; (2) engineer the V2 device where, in continuous apheresis between two animals of different age, circulating leukocytes are separated from plasma, studying how a cross-match of the age of cells and plasma influences tissue maintenance and repair; (3) engineer the V3 device with imunoaffinity modules allowing to screen and attenuate to young – healthy levels candidate systemic proteins, using IL6 and TNF-a as the first candidates, that when elevated with age have negative effects on tissue health and regeneration.

交换输血（单采血液成分术）是管理几种疾病的常规策略，例如 镰状细胞病，新生儿溶血病，自身免疫性疾病等。有趣的是， 发表了关于异时共生的工作，手术连接了两个不同年龄的动物，等等。 最近，我们对异时血液交换的研究表明，血液单采术可以重新定位， 用作一种新模式：将老年哺乳动物的循环环境恢复到多产、年轻、 组合物，可以帮助快速和广泛地增强多个器官的维护和修复， 对抗脑、肌肉、肝脏等的许多变性疾病和炎性病症。 相对于永久性吻合的联体共生，在我们的小动物血液交换系统中， 动物可以随意连接和断开，消除共享器官的影响，适应 不像联体，其中关节循环是随机建立在约7 - 10天，我们的程序， 侵入性小且控制准确，交换量易于编程和测量; 可以准确和容易地询问效应的开始和持续时间。细胞与血浆 可以研究异时性，并且免疫亲和模块能够去除特异性抑制分子 在这种"恢复活力的"血液返回到老动物体内之前， 候选的系统性蛋白质，从年轻的循环中去除这些蛋白质会抑制组织的维持和修复。 我们将（1）确定异时血液分离术对健康影响的发生时间和持续时间， 维持肌肉、肝脏和大脑、动物性能（力量和认知）和全身细胞因子 轮廓，还定义了显着影响这些的交换血液的最小功能剂量 参数;（2）设计V2装置，其中，在不同年龄的两只动物之间的连续单采中， 循环中的白细胞从血浆中分离出来，研究细胞和血浆的年龄如何交叉匹配 影响组织维护和修复;（3）用免疫亲和模块设计V3装置， 筛选并减弱到年轻健康水平的候选系统蛋白，使用IL 6和TNF-α作为第一 候选人，当随着年龄的增长而升高时，对组织健康和再生有负面影响。