Solute carrier proteins in efferocytosis and inflammation

胞吞作用和炎症中的溶质载体蛋白

• 批准号: 10541188
• 负责人: Kodi S Ravichandran
• 金额: $ 58万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-25 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10541188
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Amino Acids; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Atherosclerosis; Autoimmune Diseases; Binding; Biological Process; Biology; Carrier Proteins; Cell Communication; Cell membrane; Cells; Cellular Membrane; Chronic; Communication; Communities; Defect; Dendritic Cells; Development; Digestion; Disease; Drug Targeting; Eating; Epithelial Cells; Evolution; Excision; Family; Family member; Fibroblasts; G-Protein-Coupled Receptors; Gene Family; Genes; Human; Human Genome; Immune system; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Insecta; Ions; Knowledge; Knowledge acquisition; Life; Ligands; Link; Macrophage; Mediating; Membrane Proteins; Modeling; Mus; Mutation; Nature; Nematoda; Organ; Organism; Pathologic; Phagocytes; Phagocytosis; Phase; Play; Process; Protein Family; Proteins; Pulmonary Inflammation; Regulation; Role; Series; Signal Transduction; Testing; Therapeutic; Tissues; Work; aerobic glycolysis; cell age; cell injury; glucose uptake; human disease; insight; member; prevent; public health relevance; receptor; solute; transcriptome sequencing; uptake; urea transporter

Abstract: SOLUTE CARRIER (SLC) PROTEINS IN EFFEROCYTOSIS AND INFLAMMATION: It is truly remarkable that our bodies turn over on average about one million cells every second of life. The cells that are turned over, predominantly by the process of apoptosis, include excess cells generated as part of normal development, used/aged cells, and damaged cells arising from disease or infections. The efficient removal of such apoptotic cells is important for ‘making space’ for replacement by living cells, preventing inflammation, maintaining the function of the tissue/organ, and in turn, a healthy organism. The efficient removal of the dying cells occurs via the process of ‘efferocytosis’, and is done by professional phagocytes (such as macrophages and immature dendritic cells) or neighboring cells (e.g. fibroblasts, epithelial cells) within a given tissue. Efferocytosis, which involves ligands on apoptotic cells and specific receptors on phagocytes, is very efficient, and actively anti-inflammatory. However, impaired clearance of apoptotic cells results in the accumulation of dead cells, and the resulting chronic inflammation linked to a number of pathological conditions such as atherosclerosis, lung inflammation, and inflammatory bowel diseases. While significant progress has been made in understanding apoptotic cell recognition and efferocytic uptake in recent years, significant gaps remain. Solute carrier (SLC) proteins are membrane proteins that selectively conduct ions, metabolites, and aminoacids across the plasma membrane, and specific internal cellular membranes. In the human genome, SLCs represent the second largest family (after the GPCRs), with ~400 SLC family members. Despite ~100 human diseases being linked to mutations in SLC genes, the SLC family is relatively understided, including in the immune system 7,8. This may in part be because the SLCs functionally characterized have often been in isolation, and not many SLCs are studied as part of a larger biological process. Recently, while studying phagocytes taking up apoptotic cells, we unexpectedly came across a coordinated regulation of >30 members of the Slc gene family (Morioka et al., Nature 2018; Perry et al, Nature Cell Biol., 2019). This proposal tests the hypothesis that SLC proteins can play key roles in different phases of efferocytosis, and that sequential use of specific SLCs during efferocytosis facilitates communication between phagocytes contributes to maintaining an anti-inflammatory state within tissues.

翻译后摘要：可溶性载体（SLC）蛋白质在细胞凋亡和炎症： 值得注意的是，我们的身体在生命的每一秒钟平均转换大约一百万个细胞。的细胞 主要是通过凋亡过程，包括作为正常细胞的一部分产生的多余细胞。 发育、使用/老化的细胞和由疾病或感染引起的受损细胞。有效清除这些 凋亡细胞对于“制造空间”以被活细胞替代、预防炎症、维持 组织/器官的功能，以及健康的生物体。死亡细胞的有效去除是通过 这是一个“吞噬”过程，由专职吞噬细胞（如巨噬细胞和未成熟的树突状细胞）完成。 细胞）或给定组织内的相邻细胞（例如成纤维细胞、上皮细胞）。胞饮作用，涉及配体 对凋亡细胞和吞噬细胞上的特异性受体，是非常有效的，并积极抗炎。然而，在这方面， 凋亡细胞的清除受损导致死细胞的积累，并导致慢性炎症 与许多病理状况如动脉粥样硬化、肺部炎症和炎症性肠 疾病虽然在理解凋亡细胞识别和凋亡细胞摄取方面取得了重大进展， 近年来，仍然存在重大差距。 溶质载体（SLC）蛋白是选择性地传导离子、代谢物和氨基酸的膜蛋白 穿过质膜和特定的内部细胞膜。在人类基因组中，SLC代表了 第二大家族（仅次于GPCR），约有400个SLC家族成员。尽管约100种人类疾病与 对于SLC基因的突变，SLC家族相对被理解，包括在免疫系统中7，8。这可以 部分是因为功能上表征的SLC通常是孤立的，并且没有多少SLC被研究为 一个更大的生物过程的一部分。最近，在研究吞噬细胞摄取凋亡细胞时， 遇到了Slc基因家族>30个成员的协调调节（Morioka等，Nature 2018;佩里等人， 自然细胞生物学，2019年）。这一提议验证了SLC蛋白可以在不同阶段发挥关键作用的假设。 在红细胞增多症期间，顺序使用特定的SLC有助于细胞间的交流。 吞噬细胞有助于维持组织内的抗炎状态。