REGULATION OF PLASMA CELL MALIGNANCY BY INSULIN AND IGF

描述(申请人描述)：多发性骨髓瘤是一种恶性疾病 浆细胞的增殖，和所有癌症一样，它是至关重要的 了解促进其新陈代谢、生长和发育的因素 死亡。研究人员已经证明多发性骨髓瘤细胞 LINE对胰岛素和IGF-1非常敏感。细胞反应 包括胰岛素受体底物-1(IRS-1)的磷酸化， 激活磷脂酰肌醇3-激酶(PI3-激酶)，增加DNA 促进乳酸盐合成和糖原合成。在……里面 此外，他们还表明，PI3-激酶丝氨酸激酶可以磷酸化 IRS-1以激素依赖的方式表达。此外，他们还观察到 胰岛素受体磷酸化PI3的催化亚单位- 磷酸化酪氨酸磷酸酶(PTPase)CD45调节的 PI3-激酶活性及胰岛素和IGF-1诱导细胞凋亡 这一过程依赖于PI3-激酶。这个 这项研究项目的目的是检验以下假设 胰岛素和IGF-1诱导骨髓瘤细胞凋亡，这一过程 依赖于PI3-激酶以及PI3-K之间新的相互作用。 KLK、CD45、IRS-1和PI3-KSK调节 细胞凋亡的过程。这个项目的长期目标是定义 胰岛素和/或IGF-1如何用于多发性骨髓瘤和/或 其他恶性肿瘤更容易受到癌症治疗的影响。具体的 要追求的目标如下。首先，他们将调查 CD45对胰岛素和IGF-1依赖的PI3的反调节作用 人骨髓瘤细胞系中的激酶活性。第二，他们会 IRS-1丝氨酸磷酸化抑制作用的研究 PI3-激酶活性。第三，他们将研究胰岛素和胰岛素样生长因子-1 依赖于细胞凋亡，并确定PI3-激酶如何调节这一过程。 总而言之，他们将研究胰岛素和IGF-1是如何转导他们的 骨髓瘤细胞中的信号，并描述这些信号的机制 荷尔蒙作用于控制程序性细胞死亡。 格雷戈里·G·弗洛因德医生是一位才华横溢、积极进取的年轻医生 最近被任命为助理教授的调查员 伊利诺伊大学医学院的病理学教授， 乌尔巴纳-香槟。这一职位为弗洛因德博士提供了相当大的 实验室空间，慷慨的机构支持和杰出的 基思·W·凯利博士的主要赞助人。凯利博士是一位 IGF-1对造血系统的调节领域，由来已久 培训初级教员的历史和大量的助学金支持 在这个奖项的期限内。因此，考虑到最先进的 伊利诺伊大学和斯特朗大学的研究设施 医学院和主要赞助商的机构支持， 弗洛因德博士有一个独特的机会，可以发展成为一名杰出的 临床医生和科学家。

DESCRIPTION (Applicant's Description): Multiple myeloma is a malignant proliferation of plasma cells, and, as with all cancers, it is critical to understand the factors which promote its metabolism, growth and death. The investigators have demonstrated that multiple myeloma cell lines are acutely sensitive to insulin and IGF-1. Cellular responses included, phosphorylation of insulin receptor substrate-1 (IRS-1), activation of phosphatidylinositol 3- kinase (PI3-kinase), increased DNA synthesis and enhanced lactate production and glycogen synthesis. In addition, they have shown that PI3-kinase serine kinase phosphorylates IRS-1 in a hormone dependent manner. Furthermore, they have observed that the insulin receptor phosphorylates the catalytic subunit of PI3- kinase, that the phosphotyrosine phosphatase (PTPase) CD45 modulates PI3-kinase activity and that insulin and IGF-1 induce apoptosis in a myeloma cell line and that this process is PI3-kinase dependent. The objective of this research project is to examine the hypothesis that insulin and IGF-1 induce apoptosis in myeloma cells, that this process is dependent on PI3- kinase and that novel interactions between PI3- kinase lipid kinase, CD45, IRS- 1 and PI3-kinase serine kinase modulate the apoptotic process. The long-term goal of this project is to define how insulin and/or IGF-1 may be used to render multiple myeloma and/or other malignancies more susceptible to cancer therapies. The Specific Aims to be pursued are as follows. First, they will investigate the counter-regulatory role of CD45 on insulin and IGF-1 dependent PI3- kinase activity in human myeloma cell lines. Second, they will characterize the inhibitory effect of IRS-1 serine phosphorylation on PI3- kinase activity. Third, they will investigate insulin and IGF-1 dependent apoptosis and determine how PI3-kinase regulates this process. In summary, they will investigate how insulin and IGF-1 transduce their signals in myeloma cells and delineate the mechanisms by which these hormones act to control programmed cell death. Dr. Gregory G. Freund is a bright and motivated young physician and investigator who has recently been appointed as an Assistant Professor of Pathology in the College of Medicine at the University of Illinois, Urbana-Champaign. This position has provided Dr. Freund with sizable laboratory space, generous institutional support and an outstanding Primary Sponsor in Dr. Keith W. Kelley. Dr. Kelley, who is an expert in the field of IGF-1 regulation of the hematopoietic system, has a long history of training junior faculty members and substantial grant support for the term of this award. Therefore, given the state-of-the-art research facilities at the University of Illinois and the strong institutional support of the College of Medicine and Primary Sponsor, Dr. Freund has a unique opportunity to develop into an outstanding clinician and scientist.