Validating the efficacy of SITREX in preventing heterotopic ossification

验证 SITREX 在预防异位骨化方面的功效

基本信息

  • 批准号:
    MR/Z503782/1
  • 负责人:
  • 金额:
    $ 18.1万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2024
  • 资助国家:
    英国
  • 起止时间:
    2024 至 无数据
  • 项目状态:
    未结题

项目摘要

After trauma such as a blast wave-induced amputation, there is a cascade of events including inflammation, angiogenesis, fibroproliferation, and chondrogenesis that collectively contribute to osteogenesis and formation of ectopic bone at the injury site. This ectopic bone, known as heterotopic ossification, can be extremely painful and debilitating - surgical resection is the only way to treat the disease. There are no effective therapeutic treatments to prevent heterotopic ossification and we believe that is in part due to the therapeutics targeting one aspect of this trauma-response cascade, after the cascade has started. When this project started we set out to develop a Trauma-Response indEX (T-REX), that would comprise of genes that changed, facilitating the development of heterotopic ossification. We hypothesised that targeting these genes, changes to which occur at the apex of this cascade, would enable identification of a therapeutic which prevented heterotopic ossification. We used a range of next generation sequencing, molecular and cell biology approaches to identify 6 genes that would comprise the first iteration of T-REX (see approach section). After delving into this further, we found that inhibiting one gene in particular, with a silencing RNA, resulted in a 70% reduction of bone formation in vitro, in cells exposed to both trauma and ossification stimuli. To make this applicable for clinical translation, we packaged this siRNA into nanoparticles that could be delivered via a hydrogel to the site of injury. This nanoparticle laden hydrogel is our product, SITREX, and the subject of this current proposal. In this grant, our objective is to validate the effectiveness of SITREX in preventing heterotopic ossification in a 3D organotypic model in vitro, and a trauma responsive heterotopic ossification model in vivo. This objective bridges the gap between the basic science research already conducted, and translational studies. Validating the efficacy of SITREX in these heterotopic ossification models in vitro and in vivo will increase the technology readiness level, and de-risk SITREX for future funders.
在诸如冲击波诱导的截肢的创伤之后,存在一系列事件,包括炎症、血管生成、纤维增生和软骨形成,这些事件共同促成损伤部位处的骨生成和异位骨的形成。这种异位骨,被称为异位骨化,可能是非常痛苦和衰弱-手术切除是治疗这种疾病的唯一方法。没有有效的治疗方法来预防异位骨化,我们认为这部分是由于在级联反应开始后,针对该创伤反应级联反应的一个方面的治疗。当这个项目开始时,我们着手开发一种创伤反应indEX(T-REX),它将由改变的基因组成,促进异位骨化的发展。我们假设,靶向这些基因,发生在这个级联反应的顶点的变化,将能够识别预防异位骨化的治疗方法。我们使用了一系列下一代测序、分子和细胞生物学方法来鉴定6个基因,这些基因将构成T-REX的第一次迭代(参见方法部分)。在进一步深入研究之后,我们发现,在暴露于创伤和骨化刺激的细胞中,特别是用沉默RNA抑制一种基因,导致体外骨形成减少70%。为了使其适用于临床翻译,我们将这种siRNA包装成纳米颗粒,可以通过水凝胶递送到损伤部位。这种载有纳米颗粒的水凝胶是我们的产品SITREX,也是本提案的主题。在这项研究中,我们的目的是验证SITREX在体外3D器官型模型和体内创伤反应性异位骨化模型中预防异位骨化的有效性。这一目标弥合了已经进行的基础科学研究与转化研究之间的差距。在体外和体内验证SITREX在这些异位骨化模型中的疗效将提高技术准备水平,并为未来的资助者降低SITREX的风险。

项目成果

期刊论文数量(0)
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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Claire Higgins其他文献

07-P006 A new <em>in situ</em> study of the cellular and molecular basis of adipogenesis using developing mouse skin
  • DOI:
    10.1016/j.mod.2009.06.289
  • 发表时间:
    2009-08-01
  • 期刊:
  • 影响因子:
  • 作者:
    Kamila Wojciechowicz;Claire Higgins;Angela Christiano;Colin Jahoda
  • 通讯作者:
    Colin Jahoda
Managing weaning problems and complementary feeding
  • DOI:
    10.1016/j.paed.2013.06.010
  • 发表时间:
    2013-08-01
  • 期刊:
  • 影响因子:
  • 作者:
    Lucy Cooke;Úna McCrann;Claire Higgins
  • 通讯作者:
    Claire Higgins
Managing common feeding difficulties in toddlers and pre-school children
  • DOI:
    10.1016/j.paed.2017.04.001
  • 发表时间:
    2017-08-01
  • 期刊:
  • 影响因子:
  • 作者:
    Lucy Cooke;Claire Higgins;Úna McCrann
  • 通讯作者:
    Úna McCrann
Self-administration of medications in inpatient postnatal women: an opportunity to empower self-care, improved medicines knowledge and adherence utilising clinical pharmacists and midwifery workforce and use of a midwife formulary
住院产后妇女的自我用药:利用临床药剂师和助产士队伍以及使用助产士处方集,增强自我护理能力、提高药物知识和依从性的机会
The Preparation and Self-Efficacy of Teachers of Students with Emotional and Behavioral Disabilities
情绪和行为障碍学生教师的准备和自我效能感
  • DOI:
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Claire Higgins
  • 通讯作者:
    Claire Higgins

Claire Higgins的其他文献

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{{ truncateString('Claire Higgins', 18)}}的其他基金

Understanding the role of skin mechanical properties in the formation of scars.
了解皮肤机械特性在疤痕形成中的作用。
  • 批准号:
    NE/T014415/1
  • 财政年份:
    2020
  • 资助金额:
    $ 18.1万
  • 项目类别:
    Research Grant
Parameters for re-engineering stump skin to alleviate pressure ulcers
重新设计残肢皮肤以减轻压疮的参数
  • 批准号:
    EP/N026845/1
  • 财政年份:
    2016
  • 资助金额:
    $ 18.1万
  • 项目类别:
    Research Grant
Understanding and Preventing Inappropriate Osteogenic Differentiation
了解和预防不适当的成骨分化
  • 批准号:
    MR/M01858X/1
  • 财政年份:
    2015
  • 资助金额:
    $ 18.1万
  • 项目类别:
    Research Grant

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