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: 7473281
• 负责人: Patrick A Zweidler-McKay
• 金额: $ 13.61万
• 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: 2004-09-06 至 2009-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7473281
• 关键词: Acute; Apoptosis; Award; B lymphoid malignancy; B-Cell Acute Lymphoblastic Leukemia; B-Cell Development; B-Lymphocytes; Binding Sites; Biological Assay; Cell Cycle Arrest; Cell Death; Cell Differentiation process; Cell Fraction; Cell Line; Cells; Chickens; Chronic Lymphocytic Leukemia; Complex; Core Facility; Custom; DNA Binding; Data; Development; Developmental Process; Faculty; Future; Gene Family; Gene Targeting; Genes; Goals; Growth; Hematopoiesis; Heterodimerization; Hodgkin Disease; Human; Human Herpesvirus 4; Knowledge; Laboratories; Ligands; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediator of activation protein; Mentors; Methods; Mus; Myelogenous; Notch Signaling Pathway; Notch signaling in hematopoiesis; Oligonucleotides; Pathway interactions; Pattern; Pear; Pediatric Hematology/Oncology; Pediatric Hospitals; Pennsylvania; Philadelphia; Physicians; Play; Reagent; Receptor Signaling; Research; Research Personnel; Research Project Grants; Role; Scientist; Signal Pathway; Signal Transduction; Staging; Stem cells; T-Lymphocyte; TCF3 gene; Testing; Therapeutic; Training; Universities; Work; base; career; cell growth; chronic leukemia; design; extracellular; insight; instructor; interest; leukemia; leukemia/lymphoma; member; myogenesis; neurogenesis; notch protein; receptor; research study; skills; tool; vasculogenesis

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受体信号通路已与多个发育过程有关，包括神经发生，血管生成，肌发生和造血。在造血中，Notch信号传导可以调节干细胞分化和增殖，髓样成熟，对于T和B淋巴细胞发育之间的细胞命运决策至关重要。此外，Notch信号传导可以诱导T细胞恶性肿瘤，最近的Notch信号传导与B细胞生长停滞和凋亡有关。作为费城儿童医院（CHOP）的小儿血液学和肿瘤学研究员，我已经开始了一个研究项目，探讨了Notch受体信号传导对人B细胞恶性肿瘤的影响。我的初步数据表明，几种人类B白血病/淋巴瘤细胞系在引起Notch配体，细胞内Notch1或Hohaty（Notch notch notch noty）下游靶基因后，会经历细胞周期停滞和细胞凋亡。在接下来的五年中，作为CHOP的讲师，我将重点关注自己的职业发展，成为一名独立的调查员。该提案将提供我将在这个指导时期实现这一目标的具体培训和科学方法。 该建议的第一个目的是确定哪些Notch途径基因在正常的人类B细胞和B细胞恶性肿瘤中表达。这将确定B细胞开发的阶段，在此阶段，Notch信号传导可能发挥作用并促进诱导Notch信号传导的设计。我的第二个目的是开发在B细胞恶性肿瘤中激活Notch信号传导的方法，这些方法将通过细胞外和细胞内均值来实现。这项工作将试图开发出一种潜在的治疗方法来针对B细胞恶性肿瘤。最终目的是阐明Notch介导的对B恶性肿瘤的作用的机制，这不仅可以洞悉细胞特异性的Notch信号途径，而且还可能揭示了操纵Notch信号通路的其他方法。 这项研究将在沃伦·皮尔博士的实验室中进行。 Pear博士是宾夕法尼亚大学（UPENN）的教职员工，对Notch受体途径的许多方面进行了研究。通过Chop＆Upenn，我可以使用广泛的核心设施和大量的教学机会。该K08奖将促进我的职业目标，即获得知识和分析技能，以确立自己是医师科学家和独立癌症研究员的知识和分析技能。