Growth Regulation and Therapy of Leukemias and Lymphomas

白血病和淋巴瘤的生长调节和治疗

• 批准号: 7122013
• 负责人: SUBBARAO BONDADA
• 金额: $ 118.55万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7122013
• 关键词: cell growth regulation; clinical research; leukemia; lymphoma

The overall goal of this program project is to understand the molecular mechanisms underlying leukemia and lymphoma development and to devise novel therapeutic strategies to control lymphoid neoplasms. There are four highly interactive projects that progress from basic studies to clinically applicable therapeutic strategies with a delicate balance between in vitro and in vivo model systems. Project 1: Cell Cycle Progression of Normal and Malignant B Cells: Dr. Snow will study the role of cell cycle regulators in the ability of CD40 to synergise with BCR to induce cell cycle progression in normal B cells. They will determine the basis of the diverse response patterns of three subgroups of B cell lymphomas to CD40 signaling and the in vivo relevance of such CD40 signaling for B lymphoma growth using transgenic mice. Porject 2: Role of egr-1 gene in the growth regulation of normal B cells and B cell lymphoma: Dr. Bondada will study the basis of B cell receptor induced down regulation of the immediate early gene, egr-1 and its relation to lymphoma growth inhibition using BKS-2, a B cell lymphoma. The importance of egr-1 for B cell development and B lymphoma growth will be studied in transgenic mice that express a dominant negative form of the egr-1 protein. Project 3: Biological chaaracterization of human leukemic stem cells (LSC): Dr. Jordan will examine the novel concept that LSC are the basis of relapse of drug treated leukemias. The growth requirement of LSC will be characterized. Modulation of pro and anti-apoptotic genes will be explored to control leukemic cell growth. Project 4: Graft-versus-tumor (GVT) activity of syngeneic/allogeneic graft versus host disease (GVHD): Dr. Bryson will determine the cellular mechanisms involved in GVHD and in GVT reaction. They will test the hypothesis that cyclosporin A induced oxidative stress directly participates in the induction of SGVHD. Cellular basis of the lack of memory in GV7- responses will be studied. Support for three Cores, a transgenic and genetically defined animal facility, histopathology and administrative core, is requested to support the rsearch in this PO1 application.

该计划项目的总体目标是了解白血病和淋巴瘤发展的分子机制，并设计控制淋巴肿瘤的新治疗策略。有四个高度互动的项目，从基础研究进展到临床适用的治疗策略，并在体外和体内模型系统之间取得微妙的平衡。项目 1：正常和恶性 B 细胞的细胞周期进展：Snow 博士将研究细胞周期调节剂在 CD40 与 BCR 协同诱导正常 B 细胞细胞周期进展的能力中的作用。他们将使用转基因小鼠确定 B 细胞淋巴瘤三个亚组对 CD40 信号传导的不同反应模式的基础，以及此类 CD40 信号传导与 B 淋巴瘤生长的体内相关性。项目 2：egr-1 的作用 正常 B 细胞和 B 细胞淋巴瘤生长调节中的基因：Bondada 博士将研究 B 细胞受体诱导的早期基因 egr-1 下调的基础及其与使用 BKS-2（一种 B 细胞淋巴瘤）的淋巴瘤生长抑制的关系。将在表达egr-1蛋白显性失活形式的转基因小鼠中研究egr-1对于B细胞发育和B淋巴瘤生长的重要性。项目 3：人类白血病干细胞 (LSC) 的生物学特征：Jordan 博士将研究 LSC 是药物治疗白血病复发的基础这一新概念。 LSC 的生长需求将被表征。将探索促凋亡基因和抗凋亡基因的调节来控制白血病细胞的生长。项目4：同基因/同种异体移植物抗宿主疾病的移植物抗肿瘤（GVT）活性 (GVHD)：Bryson 博士将确定 GVHD 和 GVT 反应中涉及的细胞机制。他们将检验环孢菌素 A 诱导的氧化应激直接参与 SGVHD 诱导的假设。将研究 GV7 反应中缺乏记忆的细胞基础。需要支持三个核心，即转基因和基因定义的动物设施、组织病理学和管理核心，以支持本 PO1 申请中的研究。