Transplant Models

移植模型

• 批准号: 7733365
• 负责人: Ronald Gress
• 金额: $ 70.74万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7733365
• 关键词: Acute; Affect; Aging; Androgens; CCL25 gene; Cell Count; Clinical; Clinical Trials; Complement; Development; Disease; Drug Formulations; Goals; HIV Infections; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Immigration; Immune; Insulin-Like Growth Factor I; Investigation; Laboratories; Link; Lymphoma; Lymphopenia; Malignant neoplasm of kidney; Modeling; Multiple Myeloma; Mus; Renal carcinoma; Signal Transduction; Stem cell transplant; T-Lymphocyte; Testing; Thymus Gland; Translating; Transplantation; Treatment-Related Cancer; Up-Regulation; Work; cancer therapy; chronic graft versus host disease; graft vs host disease; improved; leukemia; malignant breast neoplasm; novel strategies; reconstitution; research study; size; stem cell therapy; thymocyte

As noted in the goals and objectives stated for this project, it aims to create new models that test distinct hypotheses and provide new understandings for development of novel strategies in the treatment of lymphoma, myeloma, leukemia, breast cancer and renal cancer by hematopoietic stem cell transplantation. Hematopoietic stem cell transplant treatment of these diseases generally results in lymphopenia and immune compromise. The observation that in humans there is the ability to upregulate thymus function in the setting of cancer therapy-associated lymphopenia has been translated to murine models. We have initiated four parallel efforts to identify points of control in thymus function. In experiments utilizing IGF-1, which was found to upregulate thymus activity, we observed that while thymocyte precursor pool size and molecules involved in migration are affected, the critical control point was at the level of expanding maturational niches for incoming thymocytes. Cessation of androgen signaling, which also results in increased thymus activity, involved upregualtion of the molecule CCL25 which in turn enhanced immigation of thymocyte precusors into the thymus. CCL25 was found to be necessary for upregulation of thymus function in this setting. Both of these approaches for increasing thymus function and in turn enhancing T cell immune reconstitution in the setting of cancer therapy can be applied to clinical trials.

正如本项目的目标和目的所述，它旨在创建新的模型来测试不同的假设，并为通过造血干细胞移植治疗淋巴瘤、骨髓瘤、白血病、乳腺癌和肾癌的新策略的发展提供新的理解。造血干细胞移植治疗这些疾病通常导致淋巴细胞减少和免疫功能受损。在癌症治疗相关淋巴细胞减少的情况下，人类有能力上调胸腺功能，这一观察结果已被转化为小鼠模型。我们已经启动了四个平行的工作来确定胸腺功能的控制点。在利用IGF-1的实验中，我们发现IGF-1可以上调胸腺活性，我们观察到，虽然胸腺细胞前体池的大小和参与迁移的分子受到影响，但关键控制点是在扩大进入胸腺细胞的成熟生态位水平上。雄激素信号的停止也会导致胸腺活动的增加，这涉及到CCL25分子的上调，而CCL25分子的上调又会增强胸腺细胞前体向胸腺的迁移。在这种情况下，CCL25被发现是胸腺功能上调所必需的。这两种增加胸腺功能的方法，进而在癌症治疗的背景下增强T细胞免疫重建，都可以应用于临床试验。