Neutralizing the degenerate disc microenvironment to enhance the efficacy of therapeutic stem cells

中和退化的椎间盘微环境以增强治疗干细胞的功效

基本信息

  • 批准号:
    10536642
  • 负责人:
  • 金额:
    $ 53.79万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-02-01 至 2025-12-31
  • 项目状态:
    未结题

项目摘要

Abstract Low back pain is the leading cause of disability in the United States, with an estimated socioeconomic cost exceeding $100 billion each year. Intervertebral disc degeneration, a cascade of cellular, compositional, structural and compositional changes, is strongly implicated as a cause of low back pain. Current clinical approaches for treating low back pain associated with disc degeneration have limited long term efficacy as they seek only to manage symptoms without restoring native disc structure and mechanical function. There is an overwhelming clinical need for new treatment options, which target not only the symptoms of low back pain, but also the underlying causes. Mesenchymal stem cells (MSCs) are an attractive option for cell- based disc regeneration due to their safety, ease of isolation and ability to adopt phenotypes similar to those of disc nucleus pulposus cells. A major challenge to successful MSC-based disc regeneration, however, is the local cellular microenvironment, which presents conditions of limited nutrition, low oxygen, low pH, and persistent inflammation that predispose therapeutic interventions to failure. The objective of this proposal is to develop a novel biological therapy that maximizes the survival and anabolic potential of therapeutic stem cells by simultaneously neutralizing the degenerate disc microenvironment via the sustained delivery of nutrients, anti-inflammatory drugs and buffering agents. To accomplish this goal, we will leverage our newly established goat model of disc degeneration that mimics clinically relevant structural, composition and biomechanical characteristics, including tissue-level inflammation, and novel drug delivery methods to enable controlled and sustained release of biofactors that neutralize the degenerative microenvironment. In Aim 1 we will leverage our goat model define the in vivo cellular microenvironment of the disc as a function of degeneration severity, using cutting edge in situ physiological monitoring and ex vivo biomolecular assays. In Aim 2 we will optimize our novel microcapsule drug delivery system to neutralize the degenerate disc microenvironment through sustained delivery of glucose, anti- inflammatory drugs and buffering agents. In Aim 3 we will carry out short and long term in vivo studies to establish therapeutic efficacy in our goat model, including clinically-relevant pain assessments. At the conclusion of these studies we will have developed a rapidly translatable therapy that maximizes the regenerative potential of MSCs in the disc microenvironment, and established long term preclinical efficacy, thus placing us in a strong position to move towards human clinical trials.
摘要 在美国,腰痛是导致残疾的主要原因,估计会造成社会经济损失 每年超过1000亿美元。椎间盘退变,一系列的细胞,成分, 结构和组成的变化,强烈暗示是下背痛的原因。当前临床 治疗与椎间盘退变相关的下背痛的方法具有有限的长期功效, 它们仅寻求控制症状而不恢复天然椎间盘结构和机械功能。有 对新的治疗选择的压倒性临床需求,不仅针对低血糖症的症状, 背部疼痛,但也是根本原因。骨髓间充质干细胞(MSC)是一种有吸引力的细胞选择, 由于其安全性、易于分离和采用与基于椎间盘再生的表型相似的表型的能力, 椎间盘髓核细胞然而,成功的基于MSC的椎间盘再生的主要挑战是 局部细胞微环境,其呈现出营养有限、低氧、低pH的条件, 使治疗干预容易失败的持续性炎症。本提案的目的是 开发一种新的生物疗法,最大限度地提高治疗药物的生存和合成代谢潜力, 通过同时中和退化的椎间盘微环境, 输送营养素、抗炎药和缓冲剂。为了实现这一目标,我们将 利用我们新建立的山羊椎间盘退变模型, 结构、组成和生物力学特征,包括组织水平炎症,以及 能够控制和持续释放生物因子的新的药物递送方法 退化的微环境在目标1中,我们将利用我们的山羊模型定义体内细胞 椎间盘的微环境作为退变严重程度的函数,使用原位生理切割边缘 监测和离体生物分子测定。在目标2中,我们将优化我们的新型微胶囊药物递送 系统,以中和退化的椎间盘微环境,通过持续输送葡萄糖,抗- 炎性药物和缓冲剂。在目标3中,我们将进行短期和长期的体内研究, 在我们的山羊模型中建立治疗效果,包括临床相关的疼痛评估。在 通过这些研究,我们将开发出一种快速转化的治疗方法, MSC在椎间盘微环境中的再生潜力,并建立了长期的临床前 功效,从而使我们在迈向人体临床试验方面处于有利地位。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Neil Malhotra其他文献

Neil Malhotra的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Neil Malhotra', 18)}}的其他基金

Dynamic heterogeneity of nucleus pulposus cells from development to degeneration
髓核细胞从发育到退化的动态异质性
  • 批准号:
    10401258
  • 财政年份:
    2021
  • 资助金额:
    $ 53.79万
  • 项目类别:
Neutralizing the degenerate disc microenvironment to enhance the efficacy of therapeutic stem cells
中和退化的椎间盘微环境以增强治疗干细胞的功效
  • 批准号:
    10337343
  • 财政年份:
    2021
  • 资助金额:
    $ 53.79万
  • 项目类别:
Regenerative potential of embryonic notochordal nucleus pulposus progenitors
胚胎脊索髓核祖细胞的再生潜力
  • 批准号:
    9225462
  • 财政年份:
    2017
  • 资助金额:
    $ 53.79万
  • 项目类别:

相似海外基金

How novices write code: discovering best practices and how they can be adopted
新手如何编写代码:发现最佳实践以及如何采用它们
  • 批准号:
    2315783
  • 财政年份:
    2023
  • 资助金额:
    $ 53.79万
  • 项目类别:
    Standard Grant
One or Several Mothers: The Adopted Child as Critical and Clinical Subject
一位或多位母亲:收养的孩子作为关键和临床对象
  • 批准号:
    2719534
  • 财政年份:
    2022
  • 资助金额:
    $ 53.79万
  • 项目类别:
    Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
  • 批准号:
    2633211
  • 财政年份:
    2020
  • 资助金额:
    $ 53.79万
  • 项目类别:
    Studentship
A material investigation of the ceramic shards excavated from the Omuro Ninsei kiln site: Production techniques adopted by Nonomura Ninsei.
对大室仁清窑遗址出土的陶瓷碎片进行材质调查:野野村仁清采用的生产技术。
  • 批准号:
    20K01113
  • 财政年份:
    2020
  • 资助金额:
    $ 53.79万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
  • 批准号:
    2436895
  • 财政年份:
    2020
  • 资助金额:
    $ 53.79万
  • 项目类别:
    Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
  • 批准号:
    2633207
  • 财政年份:
    2020
  • 资助金额:
    $ 53.79万
  • 项目类别:
    Studentship
The limits of development: State structural policy, comparing systems adopted in two European mountain regions (1945-1989)
发展的限制:国家结构政策,比较欧洲两个山区采用的制度(1945-1989)
  • 批准号:
    426559561
  • 财政年份:
    2019
  • 资助金额:
    $ 53.79万
  • 项目类别:
    Research Grants
Securing a Sense of Safety for Adopted Children in Middle Childhood
确保被收养儿童的中期安全感
  • 批准号:
    2236701
  • 财政年份:
    2019
  • 资助金额:
    $ 53.79万
  • 项目类别:
    Studentship
A Study on Mutual Funds Adopted for Individual Defined Contribution Pension Plans
个人设定缴存养老金计划采用共同基金的研究
  • 批准号:
    19K01745
  • 财政年份:
    2019
  • 资助金额:
    $ 53.79万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Structural and functional analyses of a bacterial protein translocation domain that has adopted diverse pathogenic effector functions within host cells
对宿主细胞内采用多种致病效应功能的细菌蛋白易位结构域进行结构和功能分析
  • 批准号:
    415543446
  • 财政年份:
    2019
  • 资助金额:
    $ 53.79万
  • 项目类别:
    Research Fellowships
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了