STRUCTURAL/FUNCTION B CELL DIFFERENTIATION ANTIGENS

结构/功能 B 细胞分化抗原

• 批准号: 6490016
• 负责人: Edward A Clark
• 金额: $ 33.3万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-12-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6490016
• 关键词: B lymphocyte; BCL2 gene /protein; CD40 molecule; biological signal transduction; cell death; dendritic cells; gene expression; genetically modified animals; human tissue; immunologic memory; laboratory mouse; leukocyte activation /transformation; nuclear factor kappa beta; protein structure function; tissue /cell culture

Depending on the stage of a B cell, CD40 can a) rescue cells from cell death, b) stimulate cell survival, c) make cells susceptible or resistant to cell death, or d) induce cell death. The major goal of this proposal is to define the mechanisms by which signaling through CD40 promotes cell survival or death. We will start by defining the CD40 signaling pathways in B cell lines where CD40 induces survival vs. death, and then we will explore how downstream elements in the CD40 pathway regulate the fate of mouse immature and memory B cells, human germinal center (GC) B and memory B cells, and human dendritic cells (DCs). Our specific Aims are: 1) To test the hypothesis that distinct downstream proteins such as NF-kappaB function to determine whether CD40 induces a survival or inhibitory signal. We will compare the signaling pathways induced where CD40 rescues cells from death vs. where CD40 induces death phenotypes. We will test if CD40-induced growth arrest and death can be prevented by survival/anti-apoptotic genes such cIAP2, Bcl-X and/or A1; 2) To test the hypotheses that the anti-apoptotic Bcl-2 family member, Al, is essential for CD40 to a) rescue immature B cells from death and b) to induce and maintain memory B cells. We found that mRNA encoding the Bcl-2 family member, Al, is expressed in human GC and memory B cells, and that ligating CD40 on GC B cells increases expression of Al. Thus, Al may have a critical role in the regulation of B cell fate via CD40. Therefore, using A1-/-mice we will test the hypothesis that Al -/- B cells cannot be signaled via CD40 to proliferate or be rescued from cell death. We will also test if A1-/- mice have defective CD40-dependent memory B cell responses; 3) The generation of GCs and memory B cells involves finely tuned selection processes. In Aim 3 we will examine how CD40 and a CD40-regulated receptor, CDw150 (SLAM) expressed on GC B cells and/or memory B cells, affect cell fate including Fas-mediated cell death. In particular, we will test the hypothesis that CDw150 functions to regulate lifespan of memory B cells; 4) CD40 may either induce survival of DCS, put them at risk to die, or turn them into killers. Using approaches as in Aim 3, we will test the hypothesis that CD40 can induce dendritic cells to become more susceptible to cell death. These studies should lead to new insights into how CD40 regulates GC formation and B cell memory.

根据B细胞的不同阶段，CD40可以a)拯救细胞