The role of autophagy gene Atg16L1 in allogeneic hematopoietic stem cell transplantation - Renewal - 1

自噬基因Atg16L1在异基因造血干细胞移植中的作用 - Renewal - 1

基本信息

项目摘要

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used to treat a variety of malignant and non-malignant disorders, and involves the transfer of stem cells from the bone marrow, blood, or umbilical cord from a non-identical donor. The widespread application of this procedure is limited by the high rate of graft-versus-host disease (GVHD), a life-threatening condition that is mediated by alloreactive T cells from the transplant. Improving the procedure is dependent on identifying the mechanisms that contribute to this damaging T cell reactivity. We previously demonstrated in a preclinical mouse model of allo-HSCT that the autophagy protein ATG16L1 is essential for preventing intestinal inflammation and GVHD. Autophagy is a process by which cytosolic material is delivered to the lysosome for degradation, and is involved in maintaining cellular and tissue homeostasis. Additionally, a common polymorphism in ATG16L1 leading to a coding change (T300A) is associated with susceptibility to inflammatory bowel disease (IBD) and transplant-related mortality in allo-HSCT patients. Given the high prevalence of the T300A variant and the challenges associated with treating intestinal GVHD, addressing the mechanism by which ATG16L1 and autophagy protect against intestinal damage is a research priority. During the previous funding period, we made significant progress by demonstrating that ATG16L1 prevents necroptosis in intestinal epithelial cells (IECs) following allo-HSCT. Necroptosis is a form of programmed necrosis that has received attention as a therapeutic target for limiting the tissue damage observed in a range of inflammatory diseases. Our findings suggest that the intersection between autophagy and necroptosis can be targeted to treat GVHD, especially in high risk patients such as individuals harboring the ATG16L1T300A variant. However, the molecular basis for the interaction between ATG16L1 and necroptosis is obscure, and the upstream signals that trigger the adverse signaling events require examination. Thus, we lack detailed mechanistic understanding of the inflammatory process that is necessary to apply such strategies to allo-HSCT recipients. The goal of this proposal is to how ATG16L1 and autophagy integrate IEC-intrinsic and -extrinsic signals to block necroptosis following allo-HSCT, and determine how the T300A variant disrupts this protective function. We anticipate this knowledge will yield significant insight into GVHD pathogenesis and inform intervention strategies for improving allo-HSCT outcome.
同种异体造血干细胞移植(allogene hematopoietic stem cell transplantation, alloo - hsct)被用于治疗多种恶性肿瘤

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Ken Hashigiwa Cadwell其他文献

Ken Hashigiwa Cadwell的其他文献

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{{ truncateString('Ken Hashigiwa Cadwell', 18)}}的其他基金

Mechanisms of MRSA intestinal colonization
MRSA肠道定植机制
  • 批准号:
    10321574
  • 财政年份:
    2020
  • 资助金额:
    $ 71.93万
  • 项目类别:
Mechanisms of MRSA intestinal colonization
MRSA肠道定植机制
  • 批准号:
    9903060
  • 财政年份:
    2020
  • 资助金额:
    $ 71.93万
  • 项目类别:
Interactions between helminth colonization and the gut microbiota
蠕虫定植与肠道微生物群之间的相互作用
  • 批准号:
    10318081
  • 财政年份:
    2018
  • 资助金额:
    $ 71.93万
  • 项目类别:
Redefining the role of autophagy in bacterial disease
重新定义自噬在细菌性疾病中的作用
  • 批准号:
    10519116
  • 财政年份:
    2016
  • 资助金额:
    $ 71.93万
  • 项目类别:
Redefining the role of autophagy in bacterial disease
重新定义自噬在细菌性疾病中的作用
  • 批准号:
    10053295
  • 财政年份:
    2016
  • 资助金额:
    $ 71.93万
  • 项目类别:
Redefining the role of autophagy in bacterial disease
重新定义自噬在细菌性疾病中的作用
  • 批准号:
    10764559
  • 财政年份:
    2016
  • 资助金额:
    $ 71.93万
  • 项目类别:
Redefining the role of autophagy in bacterial disease
重新定义自噬在细菌性疾病中的作用
  • 批准号:
    10384537
  • 财政年份:
    2016
  • 资助金额:
    $ 71.93万
  • 项目类别:
The role of autophagy gene Atg16L1 in allogeneic hematopoietic stem cell transplantation - Renewal - 1
自噬基因Atg16L1在异基因造血干细胞移植中的作用 - Renewal - 1
  • 批准号:
    9915940
  • 财政年份:
    2015
  • 资助金额:
    $ 71.93万
  • 项目类别:
The role of autophagy gene Atg16L1 in allogeneic hematopoietic stem cell transplantation - Renewal - 1
自噬基因Atg16L1在异基因造血干细胞移植中的作用 - Renewal - 1
  • 批准号:
    9763726
  • 财政年份:
    2015
  • 资助金额:
    $ 71.93万
  • 项目类别:
Role of Nod2 in preventing intestinal disease downstream of microbial imbalances
Nod2 在预防微生物失衡下游肠道疾病中的作用
  • 批准号:
    9105377
  • 财政年份:
    2015
  • 资助金额:
    $ 71.93万
  • 项目类别:

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