Pathologic Signaling Pathways in AML Cells

AML 细胞中的病理信号通路

基本信息

  • 批准号:
    10553601
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-01-01 至 2024-12-31
  • 项目状态:
    已结题

项目摘要

Abstract: Acute myeloid leukemia (AML) is a serious blood cancer that affects United States Veterans and other individuals. Multiple studies have demonstrated that active signaling pathways are a necessary step to leukemic cell transformation. However, the mechanism(s) of activated signaling in FLT3 wild type AML are poorly described. We hypothesize that constitutive activation of the PI3 kinase pathway leads to activation of a complex called mammalian target of rapamycin 2 (mTORC2) which regulates diverse pathways to balance cell growth and survival in AML cells. In this proposal, we will define these signaling pathways and determine if inhibition of mTORC2 alone or in combination with other drugs will enhance survival in pre-clinical models of AML leading to new therapies for this challenging disease. 1. Objective(s): The overall objective of the research proposal is to define the mechanisms of activated cell signaling in AML cells, determine the biochemical pathways regulated by mTORC2 in AML cells and determine if inhibition of mTORC2 in pre-clinical models can increase survival of individuals with AML. 2. Research Design: We propose three Specific Aims. Specific Aim 1) Confirm that 4EBP1 is a target of MTORC2 and not MTORC1 in human AML samples and define whether MTORC2 regulates cell survival or cell growth. Specific Aim 2) Determine if mTORC2 Regulates FOXO 3 phosphorylation in AML cells to Regulate Cell Survival. Specific Aim 3) Determine if combinatorial MTORC1/MTORC2 inhibition in combination with chemotherapy or Bcl2 inhibition suppresses AML cell growth in pre- clinical models. 3. Methodology: Specific Aim 1 will primary use human AML cells and primary human AML cells in culture. Specific Aim 2 will use similar methods but also assess FOXO binding to DNA using chromatin immunoprecipitation. Specific Aim 3 will focus on studies in a xenotransplantation model of AML developed by our laboratory. 4. Findings: We anticipate confirming that mTORC2 is actually a master regulator of signaling in AML cells. In particular, we anticipate that mTORC2 regulates 4EBP1 to regulate protein translation. We also anticipate that mTORC2 regulates FOXO proteins to regulate c-Myc expression. Finally, we anticipate that mTORC2 inhibition will work alone or in combination with other therapies to inhibit AML cell survival in vivo. 5. Clinical Relationships: These studies will use primary material from patients with AML and will be used to develop a new approach to therapy of the disease.
摘要:急性髓系白血病(Acute myeloid leukemia, AML)是一种严重影响人类健康的血癌

项目成果

期刊论文数量(0)
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MARTIN CARROLL其他文献

MARTIN CARROLL的其他文献

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{{ truncateString('MARTIN CARROLL', 18)}}的其他基金

University of Pennsylvania Patient-derived Xenograft Development and Trials Center
宾夕法尼亚大学患者来源的异种移植开发和试验中心
  • 批准号:
    10733231
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
University of Pennsylvania Patient-derived Xenograft Development and Trials Center
宾夕法尼亚大学患者来源的异种移植开发和试验中心
  • 批准号:
    10733232
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Acute myeloid leukemia (AML) Research Project
急性髓系白血病(AML)研究项目
  • 批准号:
    10733236
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Pathologic Signaling Pathways in AML Cells
AML 细胞的病理信号通路
  • 批准号:
    10341044
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Pathologic Signaling Pathways in AML Cells
AML 细胞中的病理信号通路
  • 批准号:
    10010684
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Understanding and Targeting Chemotherapy Resistance in Acute Myeloid Leukemia
了解和针对急性髓系白血病的化疗耐药性
  • 批准号:
    9114538
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
Understanding and Targeting Chemotherapy Resistance in Acute Myeloid Leukemia
了解和针对急性髓系白血病的化疗耐药性
  • 批准号:
    9295847
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
Understanding and Targeting Chemotherapy Resistance in Acute Myeloid Leukemia
了解和针对急性髓系白血病的化疗耐药性
  • 批准号:
    8946188
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
Understanding and Targeting Chemotherapy Resistance in Acute Myeloid Leukemia
了解和针对急性髓系白血病的化疗耐药性
  • 批准号:
    9512555
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
(PDQ5)Integrated Genetic and Epigenetic Prognostication for Acute Myeloid Leukemi
(PDQ5)急性髓性白血病的综合遗传和表观遗传预测
  • 批准号:
    8687082
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:

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