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，并设计新的治疗策略来控制淋巴肿瘤。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，在体外和体内模型系统之间保持微妙的平衡。项目一：正常和恶性B细胞的细胞周期进程：Snow博士将研究细胞周期调节剂在CD 40与BCR协同诱导正常B细胞周期进程中的作用。他们将使用转基因小鼠确定B细胞淋巴瘤的三个亚群对CD 40信号的不同反应模式的基础，以及这种CD 40信号与B淋巴瘤生长的体内相关性。项目2：生物多样性-1的作用 基因在正常B细胞和B细胞淋巴瘤生长调节中的作用：Bondada博士将研究B细胞受体诱导的即刻早期基因下调的基础，以及使用BKS-2（一种B细胞淋巴瘤）研究其与淋巴瘤生长抑制的关系。将在表达显性负性形式的β 1 -1蛋白的转基因小鼠中研究β 1 -1对B细胞发育和B淋巴瘤生长的重要性。项目三：人类白血病干细胞（LSC）的生物学特性：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。将描述LSC的生长要求。将探索促凋亡基因和抗凋亡基因的调节以控制白血病细胞生长。项目4：同基因/异基因移植物抗宿主病的移植物抗肿瘤（GVT）活性 （GVHD）：布赖森博士将确定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GV 7反应中缺乏记忆的细胞基础。要求对三个核心（转基因和基因定义的动物设施、组织病理学和管理核心）提供支持，以支持本PO 1申请中的研究。