REGULATION OF APOPTOSIS IN THYMOCYTES AND T LYMPHOCYTES

胸腺细胞和 T 淋巴细胞凋亡的调节

• 批准号: 2756587
• 负责人: Susan A. McCarthy
• 金额: $ 14.89万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-05-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2756587
• 关键词: BCL2 gene /protein; CD3 molecule; CD4 molecule; T cell receptor; T lymphocyte; apoptosis; autoimmunity; biological signal transduction; cell differentiation; gene expression; genetically modified animals; laboratory mouse; leukocyte activation /transformation; molecular cloning; protein structure function; proteins; thymus; tissue /cell culture; western blottings

The ability of the T lymphocyte population to distinguish between "self" and "non-self" is a central characteristic of the immune system. In the T lymphocyte lineage, repertoire selection takes place primarily during the intrathymic development of T cells from their immature bone marrow-derived progenitors, but may also continue to operate on mature T cells in the peripheral tissues. Both positive and negative selection depend on the elimination of unwatned cells by a form of programmed cell death called apoptosis. Understanding the regulation of apoptotic death in these cells is thus critical to future therapeutic manipulation of the T cell repertoire. We will investigate the role of a newly characterized 16kD protein (called "P16" here, for convience) in the regulation of thymocyte and T cell apoptosis. P16 shares an antigenic epitope with Bax, a member of the Bcl-2 gene family. Bcl-2 family members are central to the regulation of apoptosis in many cell types, including T lymphocytes. P16 also physically associates with Bax in normal lymphocytes. Based on these observations, we postulate that P166 is an anti-apoptotic Bcl-2 family member that acts by heterodimerizing with Bax and inhibiting the pro-apoptotic activity of Bax in lymphocytes. We will test this working model by investigating: (1) the genetic relationship of P16 to the Bcl-2 family; (2) the developmental regulation of P16 expression; (3) the mechanism of P16 down- modulation during apoptosis; and (4) the role of P16 in regulating T cell development and apoptosis.

T淋巴细胞群区分 “自我”和“非自我”是免疫系统的一个核心特征。 系统 在T淋巴细胞谱系中， 主要发生在T细胞的胸腺内发育过程中， 他们的不成熟的骨髓来源的祖细胞，但也可能继续 对外周组织中的成熟T细胞进行手术。 两 积极和消极的选择取决于消除意料之外的 细胞通过一种叫做细胞凋亡的程序性细胞死亡的形式。 了解这些细胞中凋亡性死亡的调节是 因此对未来T细胞的治疗操作至关重要， 保留曲目。 我们将研究一个新鉴定的16 kD蛋白的作用， （为了方便，这里称为“P16”）在胸腺细胞和 T细胞凋亡。 P16与Bax共享一个抗原表位， Bcl-2基因家族 Bcl-2家族成员是 在包括T淋巴细胞在内的许多细胞类型中调节细胞凋亡。 在正常淋巴细胞中，P16也与Bax物理结合。基于 根据这些观察结果，我们推测P166是一种抗凋亡蛋白。 Bcl-2家族成员通过与Bax异二聚化起作用， 抑制淋巴细胞中Bax的促凋亡活性。 我们将 通过调查来测试这个工作模型：（1）遗传 P16与Bcl-2家族的关系;（2）P16与Bcl-2家族的发育关系; P16表达的调控;（3）P16下调的机制。 P16在调节T细胞凋亡中的作用 细胞发育和凋亡。