MerTK regulation of the PTTG and RPE phagocytosis

MerTK 对 PTTG 和 RPE 吞噬作用的调节

• 批准号: 7920056
• 负责人: Qingxian Lu
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920056
• 关键词: Adult; Affect; Apoptotic; Autoimmune Diseases; Biological Preservation; Blindness; Candidate Disease Gene; Cell Nucleus; Cells; DNA Sequence Rearrangement; Data; Defect; Degenerative Disorder; Distal; Ectopic Expression; Epithelium; Failure; Family; Fibroblast Growth Factor 2; Functional disorder; Gene Expression Profile; Gene Expression Profiling; Gene Expression Regulation; Gene Targeting; Genes; Goals; Homeostasis; Human; IL8 gene; In Vitro; Ingestion; Inherited; Investigation; Knock-out; Knockout Mice; Knowledge; Lymphocyte; Measurement; Mediating; Metaphase; Mitosis; Modeling; Molecular; Morphology; Mus; Mutant Strains Mice; Mutation; One-Step dentin bonding system; PTTG1 gene; Patients; Phagocytes; Phagocytosis; Phenotype; Photoreceptors; Physiological; Pigments; Prevalence; Protein Tyrosine Kinase; RNA Interference; Rattus; Recovery of Function; Regulation; Retina; Retinal; Retinal Degeneration; Retinitis Pigmentosa; Rod Outer Segments; Role; Sister Chromatid; Spatial Distribution; Structure; Surgeon; Testing; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vision Tests; Visual; college; human MERTK protein; in vivo; macrophage; mutant; neovascularization; null mutation; overexpression; photoreceptor degeneration; prevent; public health relevance; receptor; research study; transcription factor

DESCRIPTION (provided by applicant): My long-term goal is to elucidate the cellular and molecular mechanism by which MerTK exerts its effects on phagocytosis of the retina pigmental epithelium (RPE) cell. MerTK is a receptor-type protein tyrosine kinase, belonging to the TAM family. MerTK knockout mice develop autoimmune disease, retinitis pigmentosa (RP) in adults with characterization of defective phagocytosis of the apoptotic lymphocytes and spent retinal outer segments (OS) by macrophage and RPE cells, respectively. Photoreceptor degeneration caused by a failure of the RPE phagocytosis has been observed and intensively studied in the Royal College of Surgeons (RCS) rat, a model in which the RPE cells carry a MerTK null mutation. MerTK null also causes human RP. Both in vivo and in vitro studies showed that the MerTK receptor participated during OS ingestion. However, the molecular mechanism on how the MerTK regulate RPE phagocytosis is still not very clear. We have analyzed gene expression profile in MerTK mutant RPE and performed functional studies on the affected genes. Of those, the PTTG was dramatically upregulated by MerTK mutation and knockout one copy of PTTG in the MerTK-/- RPE partially prevented photoreceptor degeneration in vivo. We will select and focus on MerTK mediated gene regulation to study its functional role in regulation of phagocytosis. In this proposal, we project to study how the MerTK regulate PTTG and whether the PTTG affect RPE phagocytosis. We will also investigate whether structural preservation of the central photoreceptor by lower PTTG is corresponding to function recovery with ERG or OKR measurements. Our investigation will aid in one step forward to understand the molecular mechanism on the MerTK regulation of RPE functions. PUBLIC HEALTH RELEVANCE: Retinitis pigmentosa (RP) is a group of inherited retinal degenerative diseases with a worldwide prevalence of 1:3000 and a leading cause of inherited blindness. RP is caused by mutation in a group of unrelated genes, one of these is MerTK. Our experiments in this proposal aim to elucidate the molecular mechanism of the MerTK regulation on RPE phagocytosis through studies of one candidate gene under MerTK regulation, which may in turn affect RPE function. The data from these studies is expected to provide us the new knowledge and understanding of the RPE function, which will allow us to develop and implement new therapies for treatment of RP caused by RPE dysfunction.

描述（由申请人提供）：我的长期目标是阐明 MerTK 对视网膜色素上皮 (RPE) 细胞吞噬作用发挥作用的细胞和分子机制。 MerTK 是一种受体型蛋白酪氨酸激酶，属于 TAM 家族。 MerTK 敲除小鼠在成人中患上自身免疫性疾病、色素性视网膜炎 (RP)，其特征是巨噬细胞和 RPE 细胞分别对凋亡淋巴细胞和视网膜外节 (OS) 的吞噬作用有缺陷。在皇家外科学院 (RCS) 大鼠模型中观察到并深入研究了由 RPE 吞噬作用失败引起的光感受器变性，在该模型中，RPE 细胞携带 MerTK 无效突变。 MerTK null 也会导致人类 RP。体内和体外研究均表明 MerTK 受体参与 OS 摄取过程。然而，MerTK如何调节RPE吞噬作用的分子机制仍不十分清楚。我们分析了 MerTK 突变体 RPE 中的基因表达谱，并对受影响的基因进行了功能研究。其中，PTTG 因 MerTK 突变而显着上调，敲除 MerTK-/- RPE 中 PTTG 的一个副本部分阻止了体内光感受器变性。我们将选择并关注MerTK介导的基因调控来研究其在吞噬作用调控中的功能作用。在本提案中，我们计划研究MerTK如何调节PTTG以及PTTG是否影响RPE吞噬作用。我们还将研究较低 PTTG 对中央光感受器的结构保存是否与 ERG 或 OKR 测量的功能恢复相对应。我们的研究将有助于进一步了解 MerTK 调节 RPE 功能的分子机制。公共健康相关性：色素性视网膜炎 (RP) 是一组遗传性视网膜退行性疾病，全球患病率为 1:3000，是遗传性失明的主要原因。 RP是由一组不相关基因突变引起的，其中之一是MerTK。我们在本提案中的实验旨在通过研究 MerTK 调控下的一个候选基因，阐明 MerTK 调控 RPE 吞噬作用的分子机制，从而可能反过来影响 RPE 功能。这些研究的数据预计将为我们提供对 RPE 功能的新知识和理解，这将使我们能够开发和实施治疗 RPE 功能障碍引起的 RP 的新疗法。