P3 - Biology and Epidemiology of APRIL and Blys in B-cell and NHL

P3 - APRIL 和 Blys 在 B 细胞和 NHL 中的生物学和流行病学

• 批准号: 8076890
• 负责人: JAMES R CERHAN
• 金额: $ 42.55万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8076890
• 关键词: Address; B lymphoid malignancy; B-Cell Development; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; BLyS receptor; Biology; Clinical; Clinical Management; Development; Disease; Disease model; Epidemiology; Family history of; Genes; Genetic; Genetic Polymorphism; Growth; Growth Factor; Homeostasis; Immune System Diseases; Incidence; Inflammation Mediators; Inherited; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Mediating; Molecular Epidemiology; Mutation; Non-Hodgkin' s Lymphoma; Outcome; Pathogenesis; Patients; Population Sciences; Promoter Regions; Reproduction spores; Resources; Risk; Role; Science; Serum; Source; Specimen; TNF gene; Translating; Work; bis(3-bis(4-chlorophenyl)methyl-4-dimethylaminophenyl)amine; disease phenotype; follow-up; improved; member; novel therapeutic intervention; promoter; receptor

There is accumulating evidence that implicate the TNF superfamily members BLyS and APRIL, as well as their receptors, as critical factors for the growth and survival of both normal and malignant B cells. BLyS and APRIL are expressed in B-cell non-Hodgkin lymphoma (NHL) and the expression of BLyS is associated with an aggressive disease phenotype. While it is clear that BLyS expression is required for normal B cell development and homeostasis, the exact source of BLyS in the normal and malignant scenario remains to be fully elucidated. Because serum BLyS levels are elevated in a number of B cell malignancies known to have a familial incidence, it is possible that dysregulation of BLyS occurs at the genetic level. The environmental, as well as genetic, requirements that mediate BLyS expression remain to be defined, and the promoter for the BLyS gene is poorly characterized. In preliminary work generated from our UI/MC Lymphoma SPORE Developmental Projects, we have found that a polymorphism in the BLyS promoter region correlates with increased serum BLyS levels in patients with B-cell malignancies, particularly those with a family history of B-cell related cancers. Wenow propose to follow-up these findings through a new,integrated basic andpopulation science project that utilizes the specimen and epidemiology resources developed through the UI/MC Lymphoma SPORE Biospecimens Core and the Molecular Epidemiology Resource(SPORE Project 5)during the first project period. We will determine if genetic variability in BLyS, the BLySreceptors TACI, BCMA, and BAFF-R, as well as the BLySrelated TNF molecule APRIL, are associatedwith the development of NHLand the clinical outcomeof patients. In addition to our genetic studies, wealso propose to determine the role of APRIL on thebiology of NHL B cells. We hypothesize that APRIL is involvedin the growth and survival of malignant B cells andbelieve that it maycontribute to thepathogenesis of NHL. Identification of patients who have or are predisposed to elevated BLyS and APRIL levels, or those who have genetic alterations in BLyS, APRIL, or their receptors, will provide us with an opportunity to better understand the significance of these molecules in B cell malignancies and ultimately to translate these findings to improved clinical management and perhaps novel therapeutic approaches.

有积极的证据表明TNF超家族成员Blys和4月， 以及它们的受体，是正常和恶性B细胞生长和存活的关键因素。 Blys和4月在B细胞非霍奇金淋巴瘤（NHL）中表达，而Blys的表达为 与侵略性疾病表型相关。虽然很明显，Blys表达 正常的B细胞发育和稳态，正常和恶性中的Blys的确切来源 场景仍然有待充分阐明。因为在许多B细胞中，血清泡泡水平升高 已知有家族发生率的恶性肿瘤，Blys的失调可能发生在 遗传水平。环境以及介导Blys表达的要求以及遗传的要求仍然存在 定义，Blys基因的启动子的特征很差。在产生的初步工作中 从我们的UI/MC淋巴瘤孢子发育项目中，我们发现 Blys启动子区域与B细胞恶性肿瘤患者的血清BLYS水平升高相关， 特别是那些具有与B细胞相关的癌症家族史的人。 Wenow建议跟进这些 通过一个使用标本的新的，集成的基本和人口科学项目的发现 和流行病学资源通过UI/MC淋巴瘤孢子生物测量核心开发 以及第一个项目期间的分子流行病学资源（孢子项目5）。我们 将确定Blys，BlysReceptors Taci，BCMA和BAFF-R的遗传变异性是否是否 由于Blysredlys tnf分子四月与NHLAND的发展相关联 患者的临床结局。除我们的遗传研究外，Wealso还建议 四月在NHL B细胞生物学上的作用。我们假设四月参与了增长 和恶性B细胞的存活情况，并认为它可能与NHL的病原发生有关。 识别患者或易于识别升高的Blys和4月份的患者，或者 在Blys，April或其受体中进行遗传改变，将为我们提供改善的机会 了解这些分子在B细胞恶性肿瘤中的意义，并最终翻译这些分子 改善临床管理以及新型治疗方法的发现。