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.

越来越多的证据表明，TNF超家族成员BLyS和APRIL， 以及它们的受体，作为正常和恶性B细胞生长和存活的关键因子。 BLyS和APRIL在B细胞非霍奇金淋巴瘤（NHL）中表达，并且BLyS的表达在NHL中表达。 与侵袭性疾病表型相关。虽然很明显BLyS表达是必需的， 正常B细胞发育和稳态，正常和恶性肿瘤中BLyS的确切来源 情况仍有待充分阐明。由于血清BLyS水平在许多B细胞中升高， 已知恶性肿瘤具有家族发病率，BLyS的失调可能发生在 基因水平。调节BLyS表达的环境和遗传要求仍然存在 待定义，并且BLyS基因的启动子的特征很差。在初步工作中， 从我们的UI/MC淋巴瘤孢子发展项目，我们已经发现，在多态性 BLyS启动子区与B细胞恶性肿瘤患者血清BLyS水平升高相关， 特别是那些有B细胞相关癌症家族史的人。我们现在建议跟进这些问题， 通过一个新的，综合的基础和人口科学项目，利用标本， 通过UI/MC淋巴瘤孢子生物标本核心开发的流行病学资源 和分子流行病学资源（孢子项目5）在第一个项目期间。我们 将确定BLyS、BLyS受体TACI、BCMA和BAFF-R的遗传变异性， 作为BLyS相关的TNF分子APRIL，与NHL的发展相关， 患者的临床结果。除了我们的遗传学研究，我们还建议确定 APRIL对NHL B细胞生物学特性的影响我们假设APRIL参与了 和恶性B细胞的存活，并认为它可能参与NHL的发病机制。 确定具有或倾向于BLyS和APRIL水平升高的患者，或 在BLyS，APRIL或其受体中发生遗传改变，将为我们提供一个更好的机会， 了解这些分子在B细胞恶性肿瘤中的意义，并最终将这些分子 这些发现有助于改善临床管理，或许还有助于新的治疗方法。