Mechanisms regulating apoptotic cell clearance in health and disease

健康和疾病中凋亡细胞清除的调节机制

基本信息

批准号：
10554063
负责人：
Kodi S Ravichandran
金额：
$ 33.44万
依托单位：
WASHINGTON UNIVERSITY
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：
2017-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10554063
关键词：
Mechanisms regulating apoptotic cell clearance

项目摘要

Abstract It is truly remarkable that our bodies turn over/recycle about one million cells every second of life (0.1%- 0.4% of body mass daily). The cells that are turned over can include excess cells generated as part of normal development, homeostasis, used/aged cells, and damaged cells that arise from disease or infections. Although there are many forms of cell death, a large majority of these cells die via apoptosis. Professional phagocytes (such as macrophages and immature dendritic cells), or neighboring cells (fibroblasts and epithelial cells), as well as specialized phagocytes (such as Sertoli cells) mediate the removal of the dying cells. The prompt and efficient removal of cells is important at several levels, including `making space' for replacement by living cells, preventing inflammation, maintaining the function of the tissue/organ, and in turn, a healthy organism3. When apoptotic cells fail to be cleared promptly, this can lead to secondary necrosis and the release of their intracellular contents from uncleared cells, and a predilection to autoimmunity, atherosclerosis, and certain neurological pathologies. Moreover, how apoptotic cells that are often seen in actively growing tumors and after chemo-, radiation-, or immuno-therapies has relevance to immunosuppression or immune responses to the tumor derived cells. While the field of apoptotic cell clearance is exciting ,and studies to date have identified some of the basic steps, there are still large and significant gaps in our knowledge. Some of these include: why do we have so many engulfment receptors on phagocytes, are there unique signals via these receptors, can we possibly dial up the capacity for engulfment to dampen inflammation in specific disease conditions, and how does a phagocyte (such as a macrophage) take up so much excess `cargo' and still maintain its normal metabolomics, etc. While these are large questions unto itself, these are also inter-related, and over the past 15 years, our laboratory has obtained and used different tools to address these questions, and we have also significantly contributed to moving this field in several exciting directions. The overall goal of this MIRA project is to take novel approaches that will help us better define the key steps/molecular features of the apoptotic cell clearance process and also attempt to modulate the engulfment machinery for possible therapeutic benefits in disease models.

抽象的真正值得注意的是，我们的身体每秒都将大约一百万个细胞翻转/回收（0.1％ - 每天0.4％的体重）。被关闭的单元可能包括作为正常的一部分产生的过量细胞发育，体内平衡，二手/老化的细胞以及由疾病或感染引起的受损细胞。虽然细胞死亡有多种形式，这些细胞中的大部分通过细胞凋亡而死亡。专业的吞噬细胞（例如巨噬细胞和未成熟的树突状细胞）或相邻细胞（成纤维细胞和上皮细胞）以及专门的吞噬细胞（例如Sertoli细胞）介导垂死细胞的去除。提示和有效地去除细胞在多个层面上很重要，包括“造型空间”以替换为生活细胞，防止炎症，维持组织/器官的功能，然后健康有机物3。当凋亡细胞无法及时清除时，这可能导致继发性坏死，并从未清晰的细胞中释放其细胞内含量，并偏爱自身免疫性，动脉粥样硬化和某些神经病理学。此外，如何经常在积极生长的肿瘤以及化学，辐射或免疫治疗后与对肿瘤衍生细胞的免疫抑制或免疫反应。而凋亡细胞领域清除令人兴奋，迄今为止的研究已经确定了一些基本步骤，仍然很大，并且我们的知识差距很大。其中一些包括：为什么我们在吞噬细胞，是否有这些受体有独特的信号，我们可以拨打吞噬能力在特定疾病条件下抑制炎症，以及吞噬细胞如何（例如巨噬细胞）占用太多多余的“货物”，并且仍然保持正常的代谢组学等。问题本身，这些问题也相互关联，在过去的15年中，我们的实验室已经获得了，并且使用不同的工具来解决这些问题，我们也为移动这一领域做出了重大贡献在几个令人兴奋的方向上。这个MIRA项目的总体目标是采用新颖的方法，以帮助我们更好地定义了凋亡细胞清除过程的关键步骤/分子特征，也试图尝试调节吞噬机制以在疾病模型中可能获得治疗益处。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Drugging the efferocytosis process: concepts and opportunities.

DOI：
10.1038/s41573-022-00470-y
发表时间：
2022-08
期刊：
Nature reviews. Drug discovery
影响因子：
0
作者：
通讯作者：

ELMO1 signaling is a promoter of osteoclast function and bone loss.

DOI：
10.1038/s41467-021-25239-6
发表时间：
2021-08-17
期刊：
Nature communications
影响因子：
16.6
作者：
Arandjelovic S;Perry JSA;Zhou M;Ceroi A;Smirnov I;Walk SF;Shankman LS;Cambré I;Onengut-Gumuscu S;Elewaut D;Conrads TP;Ravichandran KS
通讯作者：
Ravichandran KS

Rethinking Phagocytes: Clues from the Retina and Testes.