权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目概要促炎细胞因子 TNFα 被认为是糖尿病患者骨折愈合延迟的原因。然而，关于 TNFα 抑制对骨形成的影响尚未达成共识，这表明寻找除纯 TNF 抑制剂之外具有独特功能的新药物用于糖尿病骨折愈合的需求尚未得到满足。我们的基因筛选导致 TNFR 被鉴定为颗粒体蛋白前体 (PGRN) 的新型受体（Tang 等人，Science，2011），PGRN 是一种软骨形成因子，已被证明可以治疗自身免疫性炎症性关节炎。 1 型糖尿病是最常见的自身免疫性疾病，其特征是慢性炎症和 TNFα 活性升高。虽然 TNFα 活性主要通过 TNFR1 介导，但我们很高兴地发现 PGRN 刺激的骨再生很大程度上取决于 TNFR2。这些矛盾的发现表明，再生 PGRN/TNFR2 通路在 PGRN 刺激的骨折愈合中发挥着重要作用。此外，14-3-3ε 被确定为响应 PGRN 刺激的 TNFR2 通路的一个组成部分。此外，我们还开发了一种名为Atsttrin的工程蛋白，它由PGRN的三个TNFR结合域组成，Atsttrin在炎症性关节炎中比PGRN更有效。鉴于 TNFα 升高被认为是导致糖尿病骨折愈合延迟的原因，我们假设 PGRN 和 Atsttrin 通过 a) 抑制 TNFα/TNFR1 炎症和骨吸收途径来刺激糖尿病骨折愈合； b) 将 14-3-3ε 募集到 TNFR2，然后激活骨再生途径。具体目标是： (1) 确定 PGRN，特别是其衍生物 Atsttrin 在糖尿病骨折愈合中的作用。我们将使用全身性和诱导性 PGRN 敲除小鼠来确定 PGRN 敲除是否会延迟糖尿病骨折愈合，以及重组 PGRN 和 Atsttrin 是否可以逆转它（SA#1A）；骨折愈合的哪个阶段需要 PGRN 才能成功完成糖尿病骨折愈合 (SA#1B)； PGRN，尤其是Atsttrin，对糖尿病骨折是否有治疗功效（SA#1C）。我们将使用适当的可注射水凝胶局部输送各种剂量的 PGRN 或 Atsttrin。 (2)阐明PGRN和Atsttrin刺激糖尿病骨折愈合的分子机制。我们将确定 PGRN、Atsttrin 和 TNFα 对糖尿病骨髓干细胞软骨形成、信号通路、相互作用以及对 TNFR 和 14-3-3ε (SA#2A) 的依赖性的影响；两种 TNFR 是否对于介导 PGRN 在糖尿病骨愈合中的作用很重要 (SA#2B)；以及通过诱导14-3-3ε[-/-]小鼠建立糖尿病骨折模型(SA#2C)，了解PGRN和Atsttrin的保护作用是否依赖于14-3-3ε。拟议的研究不仅将增进我们对糖尿病骨折愈合分子事件的理解，而且还可能为糖尿病骨折愈合和其他骨折愈合受损的疾病带来新的治疗干预措施。

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.