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.

正如该项目所指出的目标和目标所指出的那样，它旨在创建新的模型，以检验不同的假设，并通过造血干细胞移植的淋巴瘤，骨髓瘤，白血病，乳腺癌，乳腺癌，乳腺癌，乳腺癌，乳腺癌和肾癌的新策略提供新的理解。这些疾病的造血干细胞移植治疗通常会导致淋巴细胞减少和免疫损害。在人类中，在癌症治疗相关的淋巴细胞减少症中有能力上调胸腺功能的能力已转化为鼠模型。我们已经开始了四个平行的努力，以识别胸腺功能中的控制点。在利用IGF-1上调胸腺活性的实验中，我们观察到，尽管影响了迁移的胸腺细胞前体池的大小和分子受到影响，但关键控制点处于扩展的成熟壁ni，用于传入胸腺细胞的水平。雄激素信号的停止也导致胸腺活性增加，涉及分子CCL25的上调，进而增强了胸腺细胞前酶进入胸腺。 发现在这种情况下，CCL25对于上调胸腺功能是必需的。在癌症治疗的情况下，这两种用于提高胸腺功能的方法以及增强T细胞免疫重建的方法都可以应用于临床试验。