TRIGGERING CELL DEATH IN B CELL LYMPHOMA

触发 B 细胞淋巴瘤的细胞死亡

基本信息

批准号：
5207205
负责人：
Shoshana Levy
金额：
--
依托单位：
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

The long term goal of this project is to develop nw approaches to induce anti-proliferative effects in human B-cell lymphomas. Antibodies and synthetic peptide ligands will be used to target cell surface molecules. The hypothesis that different receptors transduce anti-proliferative signals through different signaling cascades will be tested by dissecting the pathways of cell death through two cell surface molecular complexes, (1) the antigen binding immunoglobulin receptor complex (IgR) and (2) the TAPA-1 complex with its associated molecules, CD1`9, CD21, MHC class II, and Leu-13. Cells will be triggered by antibodies to these targets to study events that precede cell death. Once cell death pathways are established for the two molecular complexes, we will test for the specific death pathways induced by human immunoglobulins that express the VH4.21 gene and by additional cell surface receptors such as CD20 and CD40. We will then test if alterations of intracellular thiols augment the anti- proliferative effects induced by antibodies against these molecular complexes. Knowledge of death pathways and physiological conditions that can affect them will be instrumental in attempting to augment the anti- proliferative effect. If indeed different pathways lead to cell death, it will be established if combined targeting of more than one receptor at a time is synergistic. In the same manner, synergy will be sought by altering physiologic conditions. To understand the physiologic role of the TAPA-1 molecule, we will attempt to clone its ligand, express it, and study the effect of the ligand on cell death. In addition to antibody targeted therapy we will evaluate if surrogate peptide ligands to cell surface receptors can be developed for targeted therapy. Recently we have demonstrated that synthetic peptide ligands can bind specifically to the IgR. Moreover, multimeric forms of these synthetic ligands were effective inducers of a signal transduction pathway that led to programmed cell death. Random peptide phage libraries will be used to test the feasibility of identifying peptide ligands to the antigen receptor of lymphoma patients. The efficacy of the surrogate peptide ligands will be tested and compared to that of antibodies in vitro in a B- lymphoma cell line. SCID mice will be used to test the effect of the anti-proliferative antibodies and peptide ligands and to t e st for synergy in vivo between the cell death pathways they induce. Optimal administration routes and schedules for synthetic peptides will be developed and pharmacokinetics, biodistribution and efficacy will be tested. Likewise, physiologic conditions that may augment the anti-proliferative effect of antibodies and synthetic peptides will be tested in the SCID mice.

该项目的长期目标是开发新的方法来诱导人 B 细胞淋巴瘤的抗增殖作用。抗体和合成肽配体将用于靶向细胞表面分子。不同受体转导抗增殖作用的假说通过不同信号级联的信号将通过解剖进行测试通过两个细胞表面分子复合物的细胞死亡途径， (1) 抗原结合免疫球蛋白受体复合物 (IgR) 和 (2) TAPA-1 复合物及其相关分子、CD1`9、CD21、MHC II 类、和亮氨酸13。这些目标的抗体会触发细胞研究细胞死亡之前的事件。一旦细胞死亡途径为两种分子复合物建立，我们将测试具体的表达 VH4.21 的人免疫球蛋白诱导的死亡途径基因以及其他细胞表面受体，例如 CD20 和 CD40。我们然后将测试细胞内硫醇的改变是否会增强抗- 针对这些分子的抗体诱导的增殖效应复合物。了解死亡途径和生理条件可以影响他们将有助于试图增强反增殖作用。如果确实有不同的途径导致细胞死亡，那么如果联合靶向多个受体，则将建立时间是协同的。以同样的方式，将寻求协同作用改变生理条件。了解其生理作用 TAPA-1分子，我们将尝试克隆它的配体，表达它，并研究配体对细胞死亡的影响。除了抗体靶向治疗外，我们还将评估替代药物是否有效可以开发细胞表面受体的肽配体用于靶向治疗。最近我们已经证明合成肽配体可以与 IgR 特异性结合。此外，这些的多聚体形式合成配体是信号转导途径的有效诱导剂这导致了程序性细胞死亡。随机肽噬菌体文库将是用于测试鉴定抗原肽配体的可行性淋巴瘤患者的受体。替代肽的功效配体将在 B-体外进行测试并与抗体进行比较淋巴瘤细胞系。 SCID小鼠将用于测试抗增殖的效果抗体和肽配体并测试它们之间的体内协同作用它们诱导的细胞死亡途径。最佳给药途径和将制定合成肽的时间表和药代动力学，将测试生物分布和功效。同样，生理可能增强抗体的抗增殖作用的条件和合成肽将在 SCID 小鼠中进行测试。