Impact of TPO Treatment on Bone Healing and Angiogenesis in Type 2 Diabetes

TPO 治疗对 2 型糖尿病骨愈合和血管生成的影响

基本信息

  • 批准号:
    10383641
  • 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:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-07-01 至 2022-06-30
  • 项目状态:
    已结题

项目摘要

Currently, 1 in 4 veterans receiving VA care is diabetic, and over 70% are overweight or obese and at risk of developing diabetes. Diabetes is a risk factor for impaired fracture healing and numerous studies have demonstrated increased frequency of non-union, partial union, or delayed union in diabetic patients as compared to non-diabetic patients. Diabetic patients have impaired microcirculation which is partially responsible for these fracture complications. In the case of non-union, additional interventions are required such as bone grafting techniques. The gold standard for grafting to achieve bone union is the use of autograft from the patient's hip, which may not always achieve healing. Additionally, the harvest of bone often leaves patients with a painful donor site that may not resolve. Therefore, orthopaedic surgeons desire a biologic enhancement for bone healing that does not require the harvesting of iliac crest bone. Local placement of bone morphogenetic proteins (BMPs) is the only FDA approved biological option capable of healing non-unions. BMPs, although potent in promoting bone regeneration, have been associated with several side effects, including a link with cancer. Therefore, there is a great need for new therapies that heal bone with improved safety profiles. Recently, we found that thrombopoietin [TPO, a megakaryocyte (MK) growth factor] could heal critical-sized bone defects in mice, rats and pigs, as well as, if not better than, BMP-2. The long-term goal of this work is to determine whether thrombopoietic agents could serve as novel therapies for bone healing. Our studies as well as the literature show that TPO increases pathways associated with angiogenesis, increases hematopoietic cell populations, including osteoclasts (OCs) and MKs, and increases osteoblasts (OBs) and bone formation, the latter is indirectly through MK-mediated OB proliferation. Based on these ideas, we hypothesize that TPO accelerates bone healing in type 2 diabetes (T2D) by stimulating angiogenesis which has the direct benefit of delivering mesenchymal and hematopoietic cells that mediate wound healing. In Aim 1, we will assess the therapeutic effects of TPO on bone healing in diet-induced obesity with hyperglycemia, hyperinsulinemia, and glucose intolerance (T2D). Mice on a C57BL/6 background will be fed a low fat diet (LFD) or a high fat diet (HFD), will undergo a segmental bone defect surgery, will be treated with saline (negative control), BMP-2 (positive control), or TPO (experimental group), and bone healing assessed. In Aim 2, we will demonstrate the role of TPO in stimulating angiogenesis/vasculogenesis. This will be accomplished by characterizing angiogenesis/vasculogenesis in mice from Aim 1, as well as in mice in which the TPO receptor has been selectively knocked out of endothelial cells (ECs). We will also conduct a series of in vitro studies to assess the impact of TPO treatment as well as secreted factors from MKs on EC function to begin dissecting the mechanisms responsible. Successful accomplishment of these Aims will demonstrate the utility of using TPO for improving bone healing in diabetic patients. This project has high translational potential as thrombopoietic agents are currently FDA approved for treatment of low platelet numbers. Therefore, the regulatory pathway for obtaining FDA approval for a new indication, fracture healing, is easier than it would be for a compound or biologic which has never been used in patients. Finally, demonstrating the mechanism by which TPO stimulates angiogenesis will be important for determining whether other downstream targets should also be evaluated for therapeutic efficacy.
目前,四分之一接受VA护理的退伍军人患有糖尿病,超过70%的人超重或肥胖, 患糖尿病的风险。糖尿病是骨折愈合受损的危险因素,许多研究表明, 显示糖尿病患者骨不连、部分愈合或延迟愈合的频率增加, 与非糖尿病患者相比。糖尿病患者微循环受损, 造成了这些骨折并发症在骨不连的情况下,需要进行额外的干预 例如骨移植技术。 移植骨愈合的金标准是使用患者髋关节的自体移植物, 并不总能治愈。此外,骨的采集通常会给患者留下痛苦的供体 可能无法解决的网站。因此,整形外科医生希望骨愈合的生物增强 不需要采集髂嵴骨。骨形态发生蛋白的局部放置 骨形态发生蛋白(BMP)是FDA批准的唯一能够治愈骨不连的生物学选择。BMP虽然在 促进骨再生,与几种副作用有关,包括与癌症有关。 因此,非常需要具有改善的安全性特征的愈合骨的新疗法。最近我们 发现血小板生成素[TPO,一种巨核细胞(MK)生长因子]可以治愈临界大小的骨缺损, 小鼠、大鼠和猪,以及如果不比BMP-2更好的话。这项工作的长期目标是确定 血小板生成剂是否可以作为骨愈合的新疗法。 我们的研究以及文献表明,TPO增加了与血管生成相关的途径, 增加造血细胞群,包括破骨细胞(OC)和MK,并增加成骨细胞 (OBs)而骨形成是间接通过MK介导的成骨细胞增殖。基于这些想法, 我们假设TPO通过刺激血管生成加速2型糖尿病(T2 D)的骨愈合 其具有递送介导伤口愈合的间充质和造血细胞的直接益处。 在目的1中,我们将评估TPO对饮食诱导的肥胖症患者骨愈合的治疗作用, 高血糖症、高胰岛素血症和葡萄糖耐受不良(T2 D)。C57 BL/6背景上的小鼠将被喂食 低脂饮食(LFD)或高脂饮食(HFD),将接受节段性骨缺损手术,将接受以下治疗: 生理盐水(阴性对照)、BMP-2(阳性对照)或TPO(实验组),并评估骨愈合。 在目标2中,我们将证明TPO在刺激血管生成/血管发生中的作用。这将是 通过表征来自Aim 1的小鼠以及其中 TPO受体已被选择性地敲除出内皮细胞(EC)。我们亦会进行一系列 评估TPO处理以及MK分泌因子对EC功能的影响的体外研究, 开始剖析机制负责。 这些目标的成功实现将证明TPO用于改善骨的效用 治疗糖尿病患者。该项目具有很高的转化潜力,因为血小板生成剂目前 FDA批准用于治疗低血小板数量。因此,获得FDA的监管途径 批准一个新的适应症,骨折愈合,比批准一个化合物或生物制剂更容易, 从未用于患者。最后,证明TPO刺激血管生成的机制将有助于 对于确定其他下游靶点是否也应该进行治疗性评价是重要的。 功效

项目成果

期刊论文数量(5)
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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Melissa A Kacena其他文献

Melissa A Kacena的其他文献

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{{ truncateString('Melissa A Kacena', 18)}}的其他基金

RR&D Research Career Scientist Award Application
RR
  • 批准号:
    10754152
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
"Novel therapeutic approaches to improve fracture healing while reducing pain behavior"
“改善骨折愈合同时减少疼痛行为的新治疗方法”
  • 批准号:
    10609035
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
"Novel therapeutic approaches to improve fracture healing while reducing pain behavior"
“改善骨折愈合同时减少疼痛行为的新治疗方法”
  • 批准号:
    10426446
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Osteomacs and megakaryocytes interact to regulate hematopoietic stem cell function
骨巨细胞和巨核细胞相互作用调节造血干细胞功能
  • 批准号:
    10212373
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Angiogenic Therapy: Novel Approaches to Enhance Bone Regeneration in Aging - LOAD
血管生成疗法:增强衰老过程中骨再生的新方法 - LOAD
  • 批准号:
    10711847
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Osteomacs and megakaryocytes interact to regulate hematopoietic stem cell function
骨巨细胞和巨核细胞相互作用调节造血干细胞功能
  • 批准号:
    9764740
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Angiogenic Therapy: Novel Approaches to Enhance Bone Regeneration in Aging - AD/ADRD
血管生成疗法:增强衰老过程中骨再生的新方法 - AD/ADRD
  • 批准号:
    10711880
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
ShEEP Request for a Kubtec XPERT 80 Shielded Cabinet X-ray System
ShEEP 请求 Kubtec XPERT 80 屏蔽柜 X 射线系统
  • 批准号:
    9796215
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Angiogenic Therapy: Novel Approaches to Enhance Bone Regeneration in Aging
血管生成疗法:增强衰老过程中骨再生的新方法
  • 批准号:
    9757972
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Osteomacs and megakaryocytes interact to regulate hematopoietic stem cell function
骨巨细胞和巨核细胞相互作用调节造血干细胞功能
  • 批准号:
    10686056
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:

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