Targeting TNF Receptors to Inhibit Inflammation and to Prompt Bone Regeneration in Type 1 Diabetes

靶向 TNF 受体抑制炎症并促进 1 型糖尿病的骨再生

基本信息

  • 批准号:
    10915157
  • 负责人:
  • 金额:
    $ 40万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-08-03 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

Project Summary Pro-inflammatory cytokine TNFα is believed to be responsible for the delayed fracture healing observed in diabetes. However, there is no consensus on the effect of TNFα inhibition on the bone formation, indicating the unmet need in searching for new regents with unique features other than pure TNF inhibitors for diabetic fracture healing. Our genetic screen led to the identification of TNFR as the novel receptor of progranulin (PGRN) (Tang, et al, Science, 2011), a chondrogenic factor that has been shown to be therapeutic against autoimmune inflammatory arthritis. Type 1 diabetes is the most common autoimmune disease, characterized by chronic inflammation and elevated TNFα activity. Although TNFα activity is mediated primarily through TNFR1, we were excited to find that PGRN-stimulated bone regeneration largely depends on TNFR2. These paradoxical findings suggest that the regenerative PGRN/TNFR2 pathway plays a major role in PGRN-stimulated fracture healing. In addition, 14-3-3ε was identified as a component of TNFR2 pathway in response to PGRN stimulation. Further, we have developed an engineered protein named Atsttrin which is composed of three TNFR-binding domains of PGRN, and Atsttrin is more effective than PGRN in inflammatory arthritis. Given that elevated TNFα is believed to be responsible for delayed diabetic fracture healing, we hypothesize that PGRN and Atsttrin stimulate diabetic fracture healing through a) inhibition of TNFα/TNFR1 inflammatory and bone resorption pathway; and primarily b) recruitment of 14-3-3ε to TNFR2, followed by activation of bone regeneration pathway. The Specific Aims are: (1) To determine the role of PGRN, especially its derivative Atsttrin, in diabetic fracture healing. We will use both systemic and inducible PGRN knockout mice to determine whether knockout of PGRN delays diabetic fracture healing, and whether recombinant PGRN and Atsttrin can reverse it (SA#1A); which stage of fracture healing requires PGRN for successful completion of diabetic fracture healing (SA#1B); and whether PGRN, especially Atsttrin, has therapeutic efficacy in treating diabetic fracture (SA#1C). We will use an appropriate injectable hydrogel to locally deliver various dosages of PGRN or Atsttrin. (2) To elucidate the molecular mechanisms by which PGRN and Atsttrin stimulate diabetic fracture healing. We will determine the effects of PGRN, Atsttrin, and TNFα on chondrogenesis of diabetic bone marrow stem cells, signaling pathways, interplays and dependence on TNFR and 14-3-3ε (SA#2A); whether both TNFRs are important for mediating PGRN's role in diabetic bone healing (SA#2B); and whether the protective effects of PGRN and Atsttrin depend on 14-3-3ε by establishing diabetic fracture models with inducible 14-3-3ε[-/-] mice (SA#2C). Proposed studies will not only advance our understanding of the molecular events underlying diabetic fracture healing, but could also lead to novel therapeutic interventions for diabetic fracture healing and other conditions in which fracture healing is impaired.
项目总结

项目成果

期刊论文数量(18)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis.
  • DOI:
    10.1136/annrheumdis-2021-220000
  • 发表时间:
    2021-12
  • 期刊:
  • 影响因子:
    27.4
  • 作者:
    Fu W;Hettinghouse A;Chen Y;Hu W;Ding X;Chen M;Ding Y;Mundra J;Song W;Liu R;Yi YS;Attur M;Samuels J;Strauss E;Leucht P;Schwarzkopf R;Liu CJ
  • 通讯作者:
    Liu CJ
Digoxin targets low density lipoprotein receptor-related protein 4 and protects against osteoarthritis.
  • DOI:
    10.1136/annrheumdis-2021-221380
  • 发表时间:
    2022-04
  • 期刊:
  • 影响因子:
    27.4
  • 作者:
    Wang, Kai-di;Ding, Xiang;Jiang, Nan;Zeng, Chao;Wu, Jing;Cai, Xian-yi;Hettinghouse, Aubryanna;Khleborodova, Asya;Lei, Zi-Ning;Chen, Zhe-Sheng;Lei, Guang-hua;Liu, Chuan-ju
  • 通讯作者:
    Liu, Chuan-ju
In Vitro Physical and Functional Interaction Assays to Examine the Binding of Progranulin Derivative Atsttrin to TNFR2 and Its Anti-TNFα Activity.
Tau deficiency inhibits classically activated macrophage polarization and protects against collagen-induced arthritis in mice.
Interaction with ERp57 is required for progranulin protection against Type 2 Gaucher disease.
  • DOI:
    10.5582/bst.2023.01022
  • 发表时间:
    2023-05-15
  • 期刊:
  • 影响因子:
    5.5
  • 作者:
    Liu Y;Zhao X;Jian J;Hasan S;Liu C
  • 通讯作者:
    Liu C
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Chuanju Liu其他文献

Chuanju Liu的其他文献

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{{ truncateString('Chuanju Liu', 18)}}的其他基金

The immunological mechanism of PGRNs anti-inflammatory effect
PGRNs抗炎作用的免疫学机制
  • 批准号:
    10912299
  • 财政年份:
    2023
  • 资助金额:
    $ 40万
  • 项目类别:
The Role of Sodium Channel Nav1.7 in Osteoarthritis - Resubmission - 1
钠通道 Nav1.7 在骨关节炎中的作用 - 重新提交 - 1
  • 批准号:
    10390155
  • 财政年份:
    2022
  • 资助金额:
    $ 40万
  • 项目类别:
A new mouse model to study GBA1 mutation-associated diseases with multiple organs involvement
研究GBA1突变相关多器官疾病的新小鼠模型
  • 批准号:
    10651885
  • 财政年份:
    2022
  • 资助金额:
    $ 40万
  • 项目类别:
A new mouse model to study GBA1 mutation-associated diseases with multiple organs involvement
研究GBA1突变相关多器官疾病的新小鼠模型
  • 批准号:
    10508985
  • 财政年份:
    2022
  • 资助金额:
    $ 40万
  • 项目类别:
Targeting TNF Receptors to Inhibit Inflammation and to Prompt Bone Regeneration in Type 1 Diabetes - Resubmission - 1
靶向 TNF 受体抑制 1 型糖尿病炎症并促进骨再生 - 重新提交 - 1
  • 批准号:
    10453563
  • 财政年份:
    2020
  • 资助金额:
    $ 40万
  • 项目类别:
Targeting TNF Receptors to Inhibit Inflammation and to Prompt Bone Regeneration in Type 1 Diabetes - Resubmission - 1
靶向 TNF 受体抑制 1 型糖尿病炎症并促进骨再生 - 重新提交 - 1
  • 批准号:
    10218061
  • 财政年份:
    2020
  • 资助金额:
    $ 40万
  • 项目类别:
Progranulin: A Novel Gene in Gaucher Diseases
颗粒体蛋白前体:戈谢病的一个新基因
  • 批准号:
    10251862
  • 财政年份:
    2017
  • 资助金额:
    $ 40万
  • 项目类别:
Progranulin: A Novel Gene in Gaucher Diseases
颗粒体蛋白前体:戈谢病的一个新基因
  • 批准号:
    10011889
  • 财政年份:
    2017
  • 资助金额:
    $ 40万
  • 项目类别:
Progranulin Intervention in Inflammatory Bowel Diseases
颗粒体蛋白前体干预炎症性肠病
  • 批准号:
    8708276
  • 财政年份:
    2013
  • 资助金额:
    $ 40万
  • 项目类别:
The Role of PGRN Growth Factor in Osteoarthritis
PGRN 生长因子在骨关节炎中的作用
  • 批准号:
    8698896
  • 财政年份:
    2013
  • 资助金额:
    $ 40万
  • 项目类别:

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相似海外基金

Dissecting Roles for Drosophila TNF and TNF Receptors in Regulating Neuronal Morphology
剖析果蝇 TNF 和 TNF 受体在调节神经元形态中的作用
  • 批准号:
    RGPIN-2019-05621
  • 财政年份:
    2022
  • 资助金额:
    $ 40万
  • 项目类别:
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Dissecting Roles for Drosophila TNF and TNF Receptors in Regulating Neuronal Morphology
剖析果蝇 TNF 和 TNF 受体在调节神经元形态中的作用
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  • 财政年份:
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Targeting TNF Receptors to Inhibit Inflammation and to Prompt Bone Regeneration in Type 1 Diabetes - Resubmission - 1
靶向 TNF 受体抑制 1 型糖尿病炎症并促进骨再生 - 重新提交 - 1
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Dissecting Roles for Drosophila TNF and TNF Receptors in Regulating Neuronal Morphology
剖析果蝇 TNF 和 TNF 受体在调节神经元形态中的作用
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  • 财政年份:
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    $ 40万
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    Discovery Grants Program - Individual
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TNF 受体的血液动力学预测 CKD 进展
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