Myc promoted changes to the glycocalyx in leukemia

Myc 促进白血病糖萼的变化

基本信息

  • 批准号:
    10221644
  • 负责人:
  • 金额:
    $ 2.95万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-16 至 2021-12-15
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY The transcription factor c-MYC (MYC) is overexpressed in a majority of human malignancies and is associated with aggressive cancer phenotypes and poor patient outcomes. Recently, MYC was implicated in promoting leukemia's evasion of the immune system by up-regulating checkpoint proteins that suppress immune cell function. However, our understanding of how MYC shapes the tumor microenvironment is incomplete. Glycosylation of cancer cells could be part of the answer. Specifically, tumor cell oligosaccharides containing sialic acid (sialosides) are known to engage Siglec receptors on white blood cells such as natural killer cells and macrophages. The Siglecs are a family of receptors that, like the checkpoint proteins PD-1 and CD47, contain signaling domains capable of preventing immune activation. Therefore, display of sialosides is a strategy employed by tumors to evade the immune system. As a transcription factor and regulator of cellular metabolism, MYC is a likely culprit behind cancer's presentation of sialosides that regulate the immune system. I found that MYC directly regulates the sialyltransferases, the enzymes that append sialic acid to oligosaccharides. This proposal builds off these findings with the goal of characterizing sialosides capable of inhibiting the immune system in models of MYC driven leukemia. Using genetic and chemical tools, I will delineate the mechanism of sialoside synthesis promoted by MYC in cancer (Aim 1). I will then study these sialosides using in vivo models of leukemia to determine how MYC's modulation of glycosylation affects macrophage function in particular, and the tumor microenvironment in general (Aim 2). A mechanistic understanding of sialoside synthesis in MYC driven leukemias, and the downstream modulation of immune function, will promote the development of novel immunotherapies targeting sialic acid and glycosylation. The project presented herein will provide me with ample opportunities to develop academic and professional skills as I continue my training to become a clinician investigator. The work I present will take place at Stanford University in the lab of Carolyn Bertozzi, a prominent chemist and glycobiologist, who will mentor me as I become an independent investigator. I will be further advised by oncologists and tumor immunologists Dean Felsher, MD PhD; and Ravi Majeti, MD PhD. The resources and environment at Stanford are ideal for supporting me toward becoming a hematologist-oncologist with my own laboratory.
项目摘要 转录因子c-MYC(MYC)在大多数人类恶性肿瘤中过表达, 具有侵袭性的癌症表型和较差的患者结果。最近,MYC被牵连到促进 白血病通过上调抑制免疫细胞的检查点蛋白来逃避免疫系统 功能然而,我们对MYC如何塑造肿瘤微环境的理解是不完整的。 癌细胞的糖基化可能是部分答案。特别是,含有肿瘤细胞寡糖的 已知唾液酸(唾液酸苷)与白色血细胞如自然杀伤细胞上Siglec受体结合 和巨噬细胞。Siglecs是一个受体家族,与检查点蛋白PD-1和CD 47一样, 含有能够阻止免疫激活的信号传导结构域。因此,唾液酸苷的显示是一个 肿瘤逃避免疫系统的策略。作为一种转录因子和调节因子, MYC可能是癌症提供唾液酸苷(sialosides)的罪魁祸首,唾液酸苷可以调节免疫系统。 系统我发现MYC直接调节唾液酸转移酶,这种酶将唾液酸附加到 低聚糖。该提案以这些发现为基础,其目标是表征能够 在MYC驱动的白血病模型中抑制免疫系统。利用基因和化学工具,我会 阐明MYC在癌症中促进唾液酸苷合成的机制(目的1)。然后我会研究这些 唾液酸苷使用白血病的体内模型来确定MYC对糖基化的调节如何影响 特别是巨噬细胞功能,以及一般的肿瘤微环境(Aim 2)。一种机械的 理解MYC驱动的白血病中唾液酸苷的合成,以及免疫调节的下游调节。 功能,将促进以唾液酸和糖基化为靶点的新型免疫疗法的发展。 本项目将为我提供充分的机会,发展学术和专业知识。 在我继续训练成为一名临床研究员的过程中,我需要掌握各种技能。我所展示的工作将在斯坦福大学进行 卡罗琳·贝尔托齐的实验室,她是一位杰出的化学家和糖生物学家, 成为独立调查员。我将进一步咨询肿瘤学家和肿瘤免疫学家迪恩 Felsher,MD PhD;和Ravi Majeti,MD PhD。斯坦福大学的资源和环境非常适合 支持我成为一名拥有自己实验室的血液肿瘤学家。

项目成果

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Benjamin Arthur Humphers Smith其他文献

Benjamin Arthur Humphers Smith的其他文献

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{{ truncateString('Benjamin Arthur Humphers Smith', 18)}}的其他基金

Myc promoted changes to the glycocalyx in leukemia
Myc 促进白血病糖萼的变化
  • 批准号:
    9759494
  • 财政年份:
    2019
  • 资助金额:
    $ 2.95万
  • 项目类别:

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