Prostaglandin Pathways in T Cell Development

T 细胞发育中的前列腺素通路

• 批准号: 6534337
• 负责人: LISA M SPAIN
• 金额: $ 22.94万
• 依托单位: AMERICAN NATIONAL RED CROSS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6534337
• 关键词: T lymphocyte; biological signal transduction; cell differentiation; dendritic cells; laboratory mouse; leukopoiesis; natural killer cells; organ culture; prostaglandin endoperoxide synthase; prostaglandins; thymus

DESCRIPTION (Adapted from the Investigator's abstract): Prostaglandins (PGs) are lipid-derived hormones involved in rapid, localized cellular responses. Their synthesis is catalyzed by the action of the PG-H synthases, (cyclooxygenases COX-1 and -2). The non-steroidal anti-inflammatory drugs (NSAIDs), which are used for treating inflammatory diseases including arthritis; pain, clotting disorders, and cancer inhibit these enzymes. Despite the widespread use of NSAIDs, our understanding of PG function during physiological and pathological processes is incomplete. Using COX-1 and COX-2 deficient mice, and normal fetal thymus treated with NSAIDs and PG analogs in organ culture the investigator demonstrated a critical role for PGs in T-cell development. The constitutively expressed COX-1 enzyme was required for efficient T-cell development at the CD4-8- to CD4+8+ transition. COX-2 was specifically expressed in a subset of medullary epithelial cells. COX-2 was required during two steps of T-cell development, early thymocyte proliferation and differentiation, during maturation to the CD4 helper lineage. The applicant's goal is to understand the role of PG signaling in T-cell differentiation and selection. To achieve this, the investigator will first determine which cells produce and respond to PGs, and which molecules are involved in PG response and regulation. Whether PGs play a role in gamma-delta T-cell, NK T-cell, NK cell, and thymic dendritic cell development will be determined. Finally, whether PGs mediate their action by promoting cellular survival, proliferation or differentiation, will be determined. These questions will be addressed using COX-1, COX-2, and prostanoid-receptor deficient mice and fetal thymic organ culture.

描述（改编自调查员的摘要）：前列腺素（PGS） 是脂质衍生的激素参与快速，局部细胞反应。 它们的合成是由PG-H合酶的作用催化的 （环氧酶Cox -1和-2）。非甾体类抗炎药 （NSAIDS），用于治疗包括 关节炎;疼痛，凝结疾病和癌症抑制这些酶。尽管 NSAID的广泛使用，我们对PG功能的理解 生理和病理过程是不完整的。使用COX-1和COX-2 不足的小鼠和用NSAID和PG类似物处理的正常胎儿胸腺 器官培养研究者在T细胞中证明了PGS的关键作用 发展。需要组成表达的COX-1酶 在CD4-8-至CD4+ 8+过渡时有效的T细胞发育。 Cox-2是 特别在髓质上皮细胞的子集中表达。 Cox-2是 在T细胞发育的两个步骤中，需要早期胸腺细胞增殖 和分化，在成熟到CD4辅助谱系期间。这 申请人的目标是了解PG信号在T细胞中的作用 分化和选择。为了实现这一目标，调查人员将首先 确定哪些细胞产生并响应PG，哪些分子是 参与PG响应和调节。 PGS是否在伽马 - 戴尔塔（Gamma-Delta）中发挥作用 T细胞，NK T细胞，NK细胞和胸腺树突状细胞发育将是 决定。最后，PG是否通过促进细胞来介导其作用 将确定生存，增殖或分化。这些问题 将使用COX-1，COX-2和前列腺素受体不足的小鼠来解决 和胎儿胸腺培养。