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(分离)是几种疾病管理的常规策略，例如 镰状细胞病、新生儿溶血性疾病、自身免疫性疾病等。 发表了关于异慢性异种共生、不同年龄的两只动物的外科手术连接等方面的研究成果 最近，我们对异时血液交换的研究表明，血液分离可以重新定位和 作为一种新的方式：将老年哺乳动物的循环环境恢复到有生产力的，年轻的， 组合物，可有助于迅速和广泛地加强多个器官的维护和修复， 抗击脑、肌肉、肝脏等多种退行性疾病和炎症性疾病。 在我们的小动物血液交换系统中，与共生的永久吻合形成对比的是 动物是随意连接和断开的，消除了共享器官的影响，适应了 联合等。不同于异种共生，联合循环在7-10天内随机建立，我们的程序 侵入性较小，控制准确，交换量易于编程和测量；以及 可以准确和轻松地询问效果的开始和持续时间。细胞与血浆 可以研究异时性，免疫亲和模块能够去除特定的抑制分子 在这种“恢复活力的”血液回流到老动物之前的旧循环中；以及用于 候选系统蛋白，从年轻的循环中去除这些蛋白会抑制组织的维护和修复。 我们将(1)确定异慢性血液分离对健康和健康的影响的开始和持续时间 维持肌肉、肝脏和大脑、动物表现(力量和认知)和全身细胞因子 还定义了显著影响这些指标的交换血液的最小功能剂量 参数；(2)设计V2装置，其中，在两个不同年龄的动物之间连续分离时， 循环中的白细胞从血浆中分离出来，研究细胞和血浆年龄的交叉匹配 影响组织的维护和修复；(3)利用免疫亲和力模块设计V3设备，允许 筛选和减毒到年轻健康水平的候选系统蛋白，首先使用IL6和TNF-α 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。