CELLULAR ENGINEERING TO TREAT/PREVENT DISEASES OF AGING

治疗/预防衰老疾病的细胞工程

• 批准号: 6027433
• 负责人: ROBERT A GOOD
• 金额: $ 0.5万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-01-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6027433
• 关键词: B lymphocyte; T lymphocyte; aging; amyloidosis; atherosclerosis; autoimmune disorder; bone marrow transplantation; cellular pathology; diet; genetic manipulation; genetic strain; hematopoietic stem cells; histocompatibility; immunogenetics; immunoregulation; kidney disorder; laboratory mouse; leukocyte activation /transformation; liver transplantation; nutrition related tag; radiation genetics; tissue /cell culture; tissue mosaicism

We propose to continue long-term efforts to perfect bone marrow transplantation (BMT) as a means to prevent or treat many different diseases. This series of systematic experimental investigations will explore further the usefulness of bone marrow or fetal liver cell transplantation and ultimately stem cell transplantation as an experimental approach to analysis, prevention or treatment of a number of diseases and disorders not yet effectively treated. First we will explore BMT as an approach to prevention or to causation of senility in mice. We will try to prevent senility associated disease or disorders, including amyloid deposition and arthritis or arthroses, in senility accelerated mice [SAM(P)] mice. Alternatively, congenic or allogeneic BMT or congenic or allogeneic neonatal liver transplantation will be tested as a means of introducing from SAM(P) into the congenic resistant SAM(R) mice the senility accelerating propensity. Similarly, BMT will be tested as a means of causing, preventing or treating senility-associated changes and amyloidosis when BMT donors share the major histocompatibility complex (MHC) but are allogeneic to the SAM(P) mice, e.g. CBA/H or C3H/He. Alternatively, we will attempt to use donors that differ from SAM(P) at MHC, e.g. C57B1/6. BMT will also be tested as a means of preventing or treating two new models of non-inflammatory coronary vascular diseases or atherosclerosis in inbred mice. We will compare the immunological consequences of long-term BMT induced chimeric state where BMT have either been performed from autoimmune-resistant donors to mice of autoimmune-prone strains or to mice of autoimmune-resistant strains. We will also ascertain whether it is possible to treat effectively by BMT advanced, putatively irreversible kidney disease associated with autoimmunity states. Experiments will attempt to employ BMT from MHC-matched, MHC-mismatched or haploidentical donors to treat effectively advanced kidney disease by complete correction by BMT of the autoimmunity and immunologic dysregulation that led to the kidney disease in the first place. Finally, we will initiate experiments to evaluate the potential of stem cell preparations to reconstruct the entire hematopoietic and lymphoid systems and immunologic functions as an approach to correcting the genetically determined propensity to develop autoimmunities nad other diseases associated with aging and to analyze and influence the abnormal accumulations of Ly1+ B lymphocytes that occur in these autoimmune states.

我们建议继续长期努力以完善骨髓 移植（BMT）作为预防或处理许多不同的手段 疾病。 这一系列系统的实验研究将 进一步探索骨髓或胎儿肝细胞的有用性 移植并最终作为实验的干细胞移植 分析，预防或治疗多种疾病的方法 尚未有效治疗的疾病。 首先，我们将探索BMT 预防方法或小鼠衰老的因果关系。 我们将尝试 预防衰老相关疾病或疾病，包括淀粉样蛋白 沉积和关节炎或关节炎，在衰老的加速小鼠中 [SAM（P）]小鼠。 或者，先天性或同种异体BMT或同种异体或同种异体 同种异体新生儿肝移植将作为一种手段进行测试 从SAM（P）引入抗性SAM（R）小鼠 衰变加速倾向。 同样，BMT将作为一种手段进行测试 引起，预防或治疗与衰老相关的变化以及 当BMT供体共享主要的组织相容性复合物时，淀粉样变性 （MHC），但与SAM（P）小鼠具有同种异体性，例如CBA/H或C3H/HE。 或者，我们将尝试使用与Sam（P）不同的捐赠者 MHC，例如C57B1/6。 BMT也将作为预防或 治疗两种新模型的非炎性冠状动脉血管疾病或 近交小鼠的动脉粥样硬化。 我们将比较免疫学 BMT长期诱导BMT的嵌合状态的后果 是从自身免疫性供体进行自身免疫性供体的小鼠进行的 菌株或抗自身免疫性菌株的小鼠。 我们还将确定 BMT是否可以有效治疗， 与自身免疫状态相关的不可逆肾脏疾病。 实验将尝试使用MHC匹配，MHC不匹配或 单倍性供体通过 BMT完全纠正自身免疫性和免疫学 首先导致肾脏疾病的失调。 最后， 我们将启动实验以评估干细胞的潜力 重建整个造血和淋巴系统的准备 免疫学起校正遗传的方法 确定发展自身免疫的倾向 与衰老相关，分析和影响异常 在这些自身免疫性状态下发生的LY1+ B淋巴细胞的积累。