Isoforms of Human Terminal Transferase and Lymphopoiesis

人类末端转移酶同种型和淋巴细胞生成

• 批准号: 7152591
• 负责人: John Franklin Kearney
• 金额: $ 20.62万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7152591
• 关键词: Address; Adult; Age; Amino Acids; Atypical lymphocyte; B cell repertoire; B-Cell Development; B-Lymphocytes; BRCA1 gene; Cattle; Cell Cycle; Cell Ontogeny; Cells; Cessation of life; Characteristics; Chromosomes, Human, Pair 10; Cordycepin; DNA; DNA Modification Process; DNA Nucleotidylexotransferase; DNA Sequence Rearrangement; DNTT gene; Development; Doctor of Philosophy; Enzymes; Exonuclease; Gene Rearrangement; Generations; Genomics; Human; Immune system; Immunoglobulins; In Vitro; Length; Leukemic Cell; Life; Lymphocyte; Lymphoid; Lymphoid Cell; Lymphopoiesis; Malignant lymphoid neoplasm; Messenger RNA; Molecular; Monoclonal Antibodies; Mus; Myeloid Leukemia; Nuclear; Nucleotides; Numbers; Pattern; Pentostatin; Pharmaceutical Preparations; Phosphodiesterase I; Play; Polymerase; Predisposition; Process; Production; Protein Family; Protein Isoforms; Protein Overexpression; RNA Splicing; Reagent; Receptor Gene; Receptors, Antigen, B-Cell; Regulation; Role; Site; Staging; Structure; Surveys; T-Cell Receptor; T-Lymphocyte; Testing; Transferase; V(D)J Recombination; Variant; base; drug testing; fetal; genome database; immunoglobulin B; in vivo; insight; leukemia; leukemia/lymphoma; man; novel; receptor; tumorigenesis

Terminal deoxynucleotidyl transferase (TdT) is a key nuclear enzyme that is involved in the generation of diversity of T cell (TCR) and immunoglobulin B receptors (BCR). TdT is expressed at lower levels in fetal sites of lymphocyte generation, however, it is a normal component involved in the rearrangement process resulting in the production of diverse receptors in the adult. The lack of TdT activity during early development contributes to the generation of T and B cell repertoires that are less diverse than their adult counterparts. There is evidence in mice and now in man that there are alternative isoforms of TdT which have distinct and opposite activities in controlling the CDR3 lengths of T and B cell receptors. Since, virtually nothing is known about the normal patterns of expression of human TdT isoforms, the cellular and molecular aspects of TdT isoform expression by T and B cells will be studied during fetal and adult life. New monoclonal antibodies will be raised to the TdT isofroms which will permit a detailed survey of expression of these forms in normal and abnormal T and B cell development. The functional relationships of the splice variants of TdT will be analyzed and the hypothesis will be tested that the isoforms perform distinct but complementary functions during lymphocyte development. TdT activity is clearly important in the generation of diversity in both T and B cells and further elucidation of the mechanism of its action and control of expression are key to our understanding of the development of diversity in the immune system. TdT is also expressed at high levels in certain lymphoid malignancies and shares some structural characteristics with the DNA modifying family of proteins such as BRCA1, 53BP1 so that the alternative forms of TdT may play a role in tumorigenesis. The novel reagents we plan to make, together with new insights we obtain in the analysis of normal development, will permit us to analyze in more detail the expression and function of TdT in human lymphoid cells and the regulation and role of TdT expression in human leukemia and lymphoma.

末端脱氧核苷酸转移酶(TdT)是一种关键的核酶，它参与了细胞周期的调控。 T细胞(TCR)和免疫球蛋白B受体(BCR)多样性的产生。TDT表示为 然而，在胎儿部位淋巴细胞产生的较低水平，它是参与 重排过程导致成人体内产生不同的受体。缺乏 TDT在早期发育过程中的活动有助于T和B细胞库的产生， 与成年同龄人相比，它们的多样性较低。有证据表明，在老鼠身上，现在在人类身上 是TdT的替代亚型，它们在控制CDR3方面具有不同和相反的活性 T和B细胞受体的长度。因为，我们几乎完全不知道它们的正常模式 人TdT亚型的表达及TdT亚型表达的细胞和分子水平 T细胞和B细胞将在胎儿和成人生活中进行研究。将会产生新的单抗 到TDT异构体，这将允许详细调查这些形式在正常和 T、B细胞发育异常。TDT剪接变异体的功能关系如下 分析并检验这一假设，即这些亚型表现出截然不同但互补性 在淋巴细胞发育过程中发挥作用。TDT活动显然在产生 T、B细胞多样性及其作用机制和调控机制的进一步阐明 表达是我们理解免疫系统多样性发展的关键。TDT 在某些淋巴系统恶性肿瘤中也有高水平的表达，并具有一些共同的结构 具有DNA修饰蛋白家族的特征，如BRCA1，53BP1 其他形式的TDT可能在肿瘤的发生中发挥作用。我们计划制造的新型试剂， 再加上我们在分析正常发展过程中获得的新见解，将使我们能够 更详细地分析了TdT在人淋巴样细胞中的表达和功能 TdT在人类白血病和淋巴瘤中的表达调控及作用。