Notch-Mediated Apoptosis in Human B Cell Malignancies

Notch 介导的人类 B 细胞恶性肿瘤中的细胞凋亡

• 批准号: 6914994
• 负责人: Patrick A Zweidler-McKay
• 金额: $ 9.28万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6914994
• 关键词: B lymphocyte; apoptosis; biological signal transduction; cell surface receptors; clinical research; flow cytometry; gene expression; human tissue; intracellular; ligands; neoplastic growth; polymerase chain reaction; western blottings

DESCRIPTION (provided by applicant): The Notch receptor signaling pathway has been implicated in multiple developmental processes including neurogenesis, vasculogenesis, myogenesis, and hematopoiesis. In hematopoiesis, Notch signaling can regulate stem cell differentiation and proliferation, myeloid maturation and is critical in the cell fate decision between T and B lymphocyte development. In addition, Notch signaling can induce T cell malignancies and most recently Notch signaling has been associated with B cell growth arrest and apoptosis. As a Fellow in Pediatric Hematology & Oncology at the Children's Hospital of Philadelphia (CHOP), I have begun a research project exploring the effect of Notch receptor signaling in human B cell malignancies. My preliminary data shows that several human B leukemia/lymphoma cell lines undergo cell cycle arrest and apoptosis following induction of Notch signaling either by Notch ligand, intracellular Notch1 or Hairy, a Notch downstream target gene. Over the next five years, as an instructor at CHOP, I will focus on my career development into an independent investigator. This proposal will provide the specific training and scientific approaches I will use to attain this goal during this mentored period. The first aim for this proposal is to determine which Notch pathway genes are expressed in normal human B cells and B cell malignancies. This will identify stages of B cell development during which Notch signaling may play a role and facilitate the design of methods of inducing Notch signaling. My second aim is to develop methods of activating Notch signaling in B cell malignancies, which would be accomplished by both extra- and intracellular means. This work will attempt to develop a potential therapeutic approach toward B cell malignancies. The final aim is to elucidate the mechanisms of Notch-mediated effects on B malignancies, which would not only provide insight into the cell-specific Notch-signaling pathways, but also may reveal additional approaches to manipulating the Notch signaling pathway. This research will be carried out in Dr. Warren Pear's laboratory. Dr. Pear is a faculty member at the University of Pennsylvania (UPenn) where he conducts research on many aspects of the Notch receptor pathway. Through CHOP & UPenn I have access to extensive core facilities and a great diversity of didactic opportunities. This K08 award will facilitate my career goals, namely to gain the knowledge and analytic skills to establish myself as a physician scientist and independent cancer researcher over the next five years.

描述（由申请人提供）：Notch 受体信号传导途径涉及多种发育过程，包括神经发生、血管发生、肌发生和造血。在造血过程中，Notch 信号传导可以调节干细胞分化和增殖、骨髓成熟，并且对于 T 和 B 淋巴细胞发育之间的细胞命运决定至关重要。此外，Notch 信号传导可诱导 T 细胞恶性肿瘤，并且最近 Notch 信号传导与 B 细胞生长停滞和凋亡相关。作为费城儿童医院 (CHOP) 儿科血液学和肿瘤学研究员，我开始了一个研究项目，探索 Notch 受体信号传导在人类 B 细胞恶性肿瘤中的影响。我的初步数据显示，在Notch配体、细胞内Notch1或Notch下游靶基因Hairy诱导Notch信号传导后，几种人类B白血病/淋巴瘤细胞系经历了细胞周期停滞和细胞凋亡。在接下来的五年里，作为 CHOP 的讲师，我将专注于我的职业发展，成为一名独立研究者。该提案将提供我将在指导期间实现这一目标的具体培训和科学方法。 该提案的首要目标是确定哪些 Notch 通路基因在正常人类 B 细胞和 B 细胞恶性肿瘤中表达。这将确定 Notch 信号传导可能发挥作用的 B 细胞发育阶段，并有助于设计诱导 Notch 信号传导的方法。我的第二个目标是开发在 B 细胞恶性肿瘤中激活 Notch 信号传导的方法，这将通过细胞外和细胞内手段来实现。这项工作将尝试开发一种针对 B 细胞恶性肿瘤的潜在治疗方法。最终目标是阐明 Notch 介导的 B 型恶性肿瘤的作用机制，这不仅可以深入了解细胞特异性 Notch 信号传导途径，还可能揭示操纵 Notch 信号传导途径的其他方法。 这项研究将在 Warren Pear 博士的实验室进行。 Pear 博士是宾夕法尼亚大学 (UPenn) 的一名教员，他在那里对 Notch 受体通路的许多方面进行研究。通过 CHOP 和宾夕法尼亚大学，我可以使用广泛的核心设施和各种各样的教学机会。这个 K08 奖项将促进我的职业目标，即获得知识和分析技能，使自己在未来五年内成为一名医师科学家和独立癌症研究员。