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

• 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
• 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

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.

摘要 值得注意的是，我们的身体在生命的每一秒钟都有大约100万个细胞（0.1%-10%）。 每日体重的0.4%）。被翻转的细胞可以包括作为正常细胞的一部分而产生的多余细胞。 发育、稳态、使用/老化的细胞和由疾病或感染引起的受损细胞。虽然 细胞死亡有多种形式，这些细胞中的大多数通过凋亡而死亡。专职吞噬细胞 (such如巨噬细胞和未成熟树突细胞），或邻近细胞（成纤维细胞和上皮细胞），如 以及特化的吞噬细胞（如Sertoli细胞）介导死亡细胞的去除。得到迅速 有效地去除细胞在几个层面上都很重要，包括“腾出空间”， 细胞，预防炎症，维持组织/器官的功能，反过来，健康的 有机体3.当凋亡细胞不能被迅速清除时，这可导致继发性坏死， 从未清除的细胞中释放其细胞内内容物，以及对自身免疫的偏好， 动脉粥样硬化和某些神经病理学。此外，如何凋亡细胞，经常看到在 活跃生长的肿瘤和化疗、放疗或免疫治疗后， 免疫抑制或对肿瘤衍生细胞的免疫应答。而凋亡细胞领域 清除是令人兴奋的，迄今为止的研究已经确定了一些基本步骤，但仍然有大量的， 我们知识上的巨大差距。其中一些包括：为什么我们有这么多的吞噬受体， 吞噬细胞，是否有独特的信号通过这些受体，我们是否可能拨号吞噬的能力 抑制炎症在特定的疾病条件下，以及如何吞噬细胞（如巨噬细胞） 吸收了如此多的多余的“货物”，仍然保持其正常的代谢组学，等等。 问题本身，这些也是相互关联的，在过去的15年里，我们的实验室已经获得， 使用不同的工具来解决这些问题，我们也为推动这一领域的发展做出了重大贡献。 在几个令人兴奋的方向。这个MIRA项目的总体目标是采取新颖的方法， 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，并试图 调节吞噬机制，以在疾病模型中获得可能的治疗益处。

项目成果

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

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

ELMO1信号传导是破骨细胞功能和骨质流失的启动子。

• 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.

• DOI: 10.1016/j.tcb.2018.01.004
• 发表时间: 2018-04
• 期刊: Trends in cell biology
• 影响因子: 19
• 作者: Penberthy KK;Lysiak JJ;Ravichandran KS
• 通讯作者: Ravichandran KS

Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity.

• DOI: 10.1038/s41467-022-31218-2
• 发表时间: 2022-06-27
• 期刊: Nature communications
• 影响因子: 16.6

Clearing Your Mind: Mechanisms of Debris Clearance After Cell Death During Neural Development.

• DOI: 10.1146/annurev-neuro-110920-022431
• 发表时间: 2022-07-08
• 期刊: Annual review of neuroscience
• 影响因子: 13.9