Immune Triggers of Tissue Regeneration

组织再生的免疫触发因素

基本信息

批准号：
7938826
负责人：
Ajay Chawla
金额：
$ 24.04万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2010-11-14
项目状态：
已结题

项目摘要

DESCRIPTION Abstract Regenerative medicine holds immense promise for treating damaged and diseased tissues. One way to achieve this goal is to identify tissue-specific stem cells, which when introduced into organs, will stimulate regeneration. Alternatively, identification of triggers that stimulate tissue-specific progenitor cells will lead to development of small molecules or biologics to enhance the endogenous programs of tissue regeneration. Although experimental support exists for both therapeutic strategies, the molecular signals that trigger regenerative processes remain largely unknown. Although activation of the immune system, a universal response to injury, is a good candidate for triggering the tissue regeneration, the molecular pathways that directly link the immune system to progenitor cell biology remain poorly understood. We hypothesize that the ability of macrophages to penetrate tissue sites, integrate environmental inputs and transmit regenerative signals ideally positions these cells to be the central orchestrators of the regenerative response. In this model, recruited macrophages would form a mobile niche for tissue-specific progenitor cells, performing pleiotropic functions via enactment of distinct activation programs in spatially- and temporally-defined manner. Consistent with this view, our preliminary data show that deployment and activation of macrophages is essential for coordinating tissue regeneration after injury, including clearance of debris, activation and proliferation of tissue-specific stem cells, and differentiation of committed progenitors. Thus, the NIH Director's Pioneer Award Program will allow me to test the universality of these findings and to delineate molecular pathways for stimulating the endogenous programs of tissue regeneration, studies which collectively will be transformative for the field of regenerative medicine. Public Health Relevance Macrophages, the sentinels of host defense, are also the first cells to be recruited to site

描述抽象的再生医学对治疗受损和患病的组织具有巨大的希望。实现此目标的一种方法是鉴定组织特异性干细胞（将其引入器官）会刺激再生。或者，鉴定刺激组织特异性祖细胞的触发因素将导致小分子或生物制剂的发展以增强组织再生的内源性程序。尽管两种治疗策略都存在实验支持，但触发再生过程的分子信号在很大程度上尚不清楚。尽管免疫系统的激活是对损伤的普遍反应，是触发组织再生的良好候选者，但直接将免疫系统与祖细胞生物学联系起来的分子途径仍然知之甚少。我们假设巨噬细胞穿透组织部位，整合环境输入并传输再生信号的能力理想地将这些细胞定位为再生反应的中心编排。在此模型中，招募的巨噬细胞将形成组织特异性祖细胞的移动利基市场，并通过以空间和时间定义的方式制定不同的激活程序来执行多效性功能。与这种观点一致，我们的初步数据表明，巨噬细胞的部署和激活对于在损伤后协调组织再生至关重要，包括清除碎屑，组织特异性干细胞的激活和增殖，以及对递归祖细胞的分化。因此，NIH董事的先锋奖计划将使我能够测试这些发现的普遍性，并描述分子途径以刺激组织再生的内源性计划，这些研究将集体对再生医学领域进行变革。公共卫生相关性巨噬细胞是宿主防御的前哨，也是第一个被招募到现场的单元