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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：
Chuanju Liu
金额：
$ 40万
依托单位：
YALE UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/10915157
关键词：
Targeting TNF Receptors Inhibit Inflammation

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：
Annals of the rheumatic diseases
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：
ANNALS OF THE RHEUMATIC DISEASES
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.