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Clearance of Apoptotic Cells

清除凋亡细胞

基本信息

批准号：
7152596
负责人：
GLENN K. MATSUSHIMA
金额：
$ 35.21万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-12-15 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7152596
关键词：
1-Phosphatidylinositol 3-Kinase Accounting Affect Anti-Inflammatory Agents Anti-inflammatory Apoptotic Autoantibodies Autoimmune Diseases Backcrossings Biological CD36 gene Cell Communication Cell Line Cell Surface Receptors Cell surface Cells Condition Cytoplasmic Tail Defect Dinoprostone Down-Regulation Enzyme-Linked Immunosorbent Assay Goals HC phosphatase ITAM ITIM Immunoglobulin M Immunoprecipitation In Vitro Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukin-10 Kidney Lectin MAPK8 gene Mediating Monitor Mouse Cell Line Mus Mutate Mutation Outcome PTPN11 gene Pathogenesis Pathology Phagocytosis Phenylalanine Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide Phosphorylation Phosphotransferases Physiological Point Mutation Process Production Protein Sequence Analysis Purpose Reagent Receptor Protein-Tyrosine Kinases Role Route Serum Signal Pathway Signal Transduction Signal Transduction Pathway Site Systemic Lupus Erythematosus Tail Testing Tetanus Helper Peptide Time Transcription Factor AP-1 Transcriptional Activation Transducers Transgenic Mice Transgenic Organisms Tyrosine Tyrosine Kinase Domain Up-Regulation Update Wild Type Mouse Work animal facility axl receptor tyrosine kinase base clinically relevant cytokine expression cloning in vivo insight knockout animal macrophage member molecular modeling mutant novel promoter receptor response tyrosine receptor uptake

项目摘要

The purpose of this proposal is to determine the biological relevance of Mer in the clearance of apoptotic cells by macrophages and to delineate in a mechanism that would account for the recognition, phagocytosis and anti-inflammatory consequence of clearing apoptotic cells by macrophages. A mechanism for recognition and update of apoptotic cells and the signal transduction pathway(s) triggered by apoptotic cells is still poorly understood. The hypothesis is Mer/Tyro3/Axl Receptor Tyrosine Kinases facilitate phagocytosis of apoptotic cells. Our preliminary (in vivo and in vitro) studies strongly suggest that Mer, a receptor tyrosine kinase expressed on macrophages, is involved in mediating the clearance of apoptotic cells and appears to modulate an anti-inflammatory response. Mice with a mutated Mer cytoplasmic signaling kinase domain (merkd) have macrophages that re defective in suppressing pro-inflammatory cytokines such as TNF-a and are defective in phagocytizing apoptotic cells. Furthermore, we presume that this defect is clinically relevant in that merkd mice produce elevated serum IgM autoantibodies and kidney shows pathology. Indeed, evidence is accruing that apoptotic cells can contribute to pathogenesis of autoimmune diseases, and that a high burden of apoptotic cells may provide an important route to autoantibody production as it has been implicated in SLE. Investigating the process involved in recognition and clearance of apoptotic cells may provide insights towards controlling inflammation and autoimmune disorders. Towards this goal, we propose to investigate the process involved in the clearance of apoptotic cells both in vivo and in vitro through novel receptor tyrosine kinases, Axl, Mer, and Tyro3 expressed on macrophages.

本提案的目的是确定Mer在细胞凋亡清除中的生物学相关性。细胞的巨噬细胞，并描绘在一个机制，将占识别，巨噬细胞清除凋亡细胞的吞噬作用和抗炎作用。一凋亡细胞的识别和更新机制以及触发的信号转导途径对凋亡细胞的作用仍知之甚少。假设Mer/Tyro 3/Axl受体酪氨酸激酶促进凋亡细胞的吞噬作用。我们的初步（体内和体外）研究强烈表明， Mer是一种在巨噬细胞上表达的受体酪氨酸激酶，参与介导凋亡细胞，并似乎调节抗炎反应。Mer突变的小鼠细胞质信号传导激酶结构域（merkd）具有巨噬细胞，促炎细胞因子如TNF-α，并且在吞噬凋亡细胞方面有缺陷。此外，我们推测这种缺陷与merkd小鼠产生升高的血清 IgM自身抗体和肾脏病理显示。事实上，越来越多的证据表明，凋亡细胞可以有助于自身免疫性疾病的发病机制，并且凋亡细胞的高负荷可能为自身抗体的产生提供了重要途径，因为它与SLE有关。调查参与识别和清除凋亡细胞的过程可能提供对控制凋亡的见解。炎症和自身免疫性疾病。为了实现这一目标，我们建议调查的过程中，通过新型受体酪氨酸参与体内和体外凋亡细胞的清除激酶Axl、Mer和Tyro 3在巨噬细胞上表达。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The receptor tyrosine kinase MerTK regulates dendritic cell production of BAFF.

DOI：
10.1080/08916930802668586
发表时间：
2009-03
期刊：
Autoimmunity
影响因子：
3.5
作者：
Gohlke PR;Williams JC;Vilen BJ;Dillon SR;Tisch R;Matsushima GK
通讯作者：
Matsushima GK

Increased hematopoietic cells in the mertk-/- mouse peritoneal cavity: a result of augmented migration.

DOI：
10.4049/jimmunol.0902784
发表时间：
2010-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Williams JC;Wagner NJ;Earp HS;Vilen BJ;Matsushima GK
通讯作者：
Matsushima GK

MerTK regulates thymic selection of autoreactive T cells.

MerTK 调节自身反应性 T 细胞的胸腺选择。

DOI：
10.1073/pnas.0900683106
发表时间：
2009
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Wallet,MarkA;Flores,RafaelR;Wang,Yaming;Yi,Zuoan;Kroger,CharlesJ;Mathews,ClaytonE;Earp,HShelton;Matsushima,Glenn;Wang,Bo;Tisch,Roland
通讯作者：
Tisch,Roland

TAM receptors are dispensable in the phagocytosis and killing of bacteria.

DOI：
10.1016/j.cellimm.2009.06.006
发表时间：
2009
期刊：
CELLULAR IMMUNOLOGY
影响因子：
4.3
作者：
Williams, Julie C.;Craven, Robin R.;Earp, H. Shelton;Kawula, Tom H.;Matsushima, Glenn K.
通讯作者：
Matsushima, Glenn K.

Dendritic cells in systemic lupus erythematosus.

系统性红斑狼疮中的树突状细胞。