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: 10331892
• 负责人: Kodi S Ravichandran
• 金额: $ 1万
• 依托单位: UNIVERSITY OF VIRGINIA
• 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 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331892
• 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 membrane; Cells; Cellular Membrane; Chronic; Communication; Defect; Dendritic Cells; Development; Digestion; Disease; Drug Targeting; Eating; Epithelial Cells; Evolution; Excision; Family; Family member; Fibroblasts; G-Protein-Coupled Receptors; Gene Family; Gene Proteins; Genes; Human; Human Genome; Immune system; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Insecta; Intestines; Ions; Knowledge; Life; Ligands; Link; Mediating; Membrane Proteins; Modeling; Mus; Mutation; Nature; Nematoda; Organ; Organism; Pathologic; Phagocytes; Phagocytosis; Phase; Play; Process; Protein Family; Pulmonary Inflammation; Regulation; Role; Series; Signal Transduction; Testing; Therapeutic; Tissues; Work; aerobic glycolysis; base; cell age; cell injury; glucose uptake; human disease; insight; macrophage; 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.

摘要：溶质载体 (SLC) 蛋白在胞质作用和炎症中的作用： 令人惊奇的是，我们的身体在生命中平均每秒更新约一百万个细胞。这些细胞 主要通过细胞凋亡过程进行更新，包括作为正常细胞一部分产生的过量细胞 发育、使用/老化的细胞以及由疾病或感染引起的受损细胞。有效去除此类 凋亡细胞对于“腾出空间”以供活细胞替代、预防炎症、维持 组织/器官的功能，进而健康的有机体。有效去除垂死细胞是通过 “胞吞作用”的过程，由专业吞噬细胞（如巨噬细胞和未成熟的树突状细胞）完成 细胞）或给定组织内的邻近细胞（例如成纤维细胞、上皮细胞）。胞吞作用，涉及配体 对凋亡细胞和吞噬细胞上的特定受体非常有效，并且具有积极的抗炎作用。然而， 凋亡细胞的清除受损导致死亡细胞的积累，并由此产生慢性炎症 与许多病理状况有关，如动脉粥样硬化、肺部炎症和炎症性肠病 疾病。虽然在理解凋亡细胞识别和细胞摄取方面已经取得了重大进展 近年来，仍然存在巨大差距。 溶质载体 (SLC) 蛋白是选择性传导离子、代谢物和氨基酸的膜蛋白 穿过质膜和特定的细胞内膜。在人类基因组中，SLC 代表 第二大家族（仅次于 GPCR），拥有约 400 名 SLC 家族成员。尽管约 100 种人类疾病相互关联 由于 SLC 基因突变，SLC 家族的研究相对较少，包括在免疫系统中 7,8。这可能在 部分原因是 SLC 的功能特征通常是孤立的，并且没有多少 SLC 被研究为 更大的生物过程的一部分。最近，在研究吞噬细胞吞噬凋亡细胞时，我们意外地发现 发现了超过 30 个 Slc 基因家族成员的协调调节（Morioka 等人，Nature 2018；Perry 等人， 自然细胞生物学，2019）。该提案检验了 SLC 蛋白在不同阶段发挥关键作用的假设 胞吞作用，并且在胞吞作用期间连续使用特定的 SLC 促进了之间的沟通 吞噬细胞有助于维持组织内的抗炎状态。