Examination of the Role of c-Abl in B Cell Development

检查 c-Abl 在 B 细胞发育中的作用

• 批准号: 7407945
• 负责人: April M Bauer
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7407945
• 关键词: ABL1 gene; Acute Lymphocytic Leukemia; Address; Affect; Antibodies; B-Cell Development; B-Lymphocytes; Back; Bone Marrow; Cancer Etiology; Cell Lineage; Cell Proliferation; Cell physiology; Cellular biology; Chimeric Proteins; Chromosomal translocation; Chronic; Disease; Flow Cytometry; Generations; Goals; Immunity; Interleukin-7; Lead; Light; Lymphoma; Malignant Neoplasms; Mutate; Myelogenous; Outcome; Phosphorylation; Phosphotransferases; Population; Post-Translational Protein Processing; Protein Biochemistry; Proteins; Proto-Oncogene Proteins c-abl; Role; Signal Pathway; Staging; Testing; Transplantation; c-abl Proto-Oncogenes; insight

DESCRIPTION (provided by applicant): Understanding of the basic cell biology that can lead to cancer is vital to our quest to eliminate the causes of these potentially fatal diseases and find new avenues for treatment. Over 95% of Chronic Myelogenous Lymphoma and 15% of Acute Lymphocytic Leukemia can be traced back to a chromosomal translocation that fuses the cellular Abl (c-Abl) gene with the Breakage Cluster region, resulting in the Bcr-Abl protein. This fusion protein leads to cancer in B cells, but exactly how this happens is not fully understood. We have found that c-Abl is active in pro-B cells, a population of B cells vital to immunity and antibody generation, but that can give rise to lymphoma when proliferation goes unchecked. Therefore, we believe that understanding the function of c-Abl in pro-B cells will provide considerable insight into the role of Abl proteins in cancer. The specific aims of this proposal are 1) to test the hypothesis that c-Abl kinase functions in small pro-B cells; 2) to identify critical c-Abl functional domains; and 3) to identify phosphorylation substrates for c-Abl. We propose to analyze the function of c-Abl in pro-B cells by examining the subcellular localization of c-Abl in the B lineage and testing the role of c-Abl in the IL-7 signaling pathway. Additionally, we will identify which portions of c-Abl are critical for its function and identify proteins that are phosphorylated by c-Abl, a protein modification that can have significant affects on the function and stability of targets. Using bone marrow cultures and transplants, flow cytometry, and protein biochemistry we will address the function of c-Abl in the B cell lineage, with particular emphasis place on the pro-B cell stage. To understand the causes of cancer, we must understand the cellular processes that can lead to this disastrous outcome. The misregulation of key proteins can lead to unchecked cell proliferation, and may ultimately result in cancer. It is our goal to understand the normal function of the c-Abl protein, which when mutated can lead to cancer. Elucidating the normal role of this protein may shed light on the mechanisms by which its misregulation can lead to cancer.

描述（由申请人提供）：了解可能导致癌症的基本细胞生物学的理解对于我们寻求消除这些潜在致命疾病的原因并找到新的治疗途径至关重要。超过95％的慢性粒细胞性淋巴瘤和15％的急性淋巴细胞性白血病可以追溯到染色体易位，该染色体易位将细胞ABL（C-ABL）基因与断裂簇区域融合在一起，从而导致BCR-ABL蛋白。这种融合蛋白会导致B细胞中的癌症，但尚未完全理解这种情况。我们发现，C-ABL在pro-B细胞中有效，pro-b细胞是对免疫和抗体产生至关重要的B细胞群，但是当增殖不受组织时，这可能会导致淋巴瘤。因此，我们认为，了解C-ABL在pro-B细胞中的功能将为ABL蛋白在癌症中的作用提供大量见解。该提案的具体目的是1）检验C-ABL激酶在小pro-B细胞中起作用的假设； 2）确定关键的C-ABL功能域； 3）确定C-ABL的磷酸化底物。我们建议通过检查C-ABL在B谱系中的亚细胞定位并测试C-ABL在IL-7信号通路中的作用来分析C-ABL在Pro-B细胞中的功能。此外，我们将确定C-ABL的哪些部分对其功能至关重要，并鉴定由C-ABL磷酸化的蛋白质，C-ABL是一种蛋白质修饰，可能对靶标的功能和稳定性产生重大影响。使用骨髓培养物和移植，流式细胞术和蛋白质生物化学，我们将解决C-ABL在B细胞谱系中的功能，并特别强调在Pro-B细胞阶段。要了解癌症的原因，我们必须了解可能导致这种灾难性结果的细胞过程。关键蛋白质的正调可能导致未检查的细胞增殖，并最终导致癌症。我们的目标是了解C-ABL蛋白的正常功能，当突变时会导致癌症。阐明该蛋白质的正常作用可能会揭示其正调可能导致癌症的机制。