Genomic expression analyses reveal lysosomal, innate immunity proteins, as disease correlates in murine models of a lysosomal storage disorder.
Genomic expression analyses reveal lysosomal, innate immunity proteins, as disease correlates in murine models of a lysosomal storage disorder.
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DOI：
10.1371/journal.pone.0048273
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Haldar K
中科院分区：
文献类型：
--
作者：
Alam MS;Getz M;Safeukui I;Yi S;Tamez P;Shin J;Velázquez P;Haldar K
C 型尼曼-匹克 (NPC) 病是一种罕见的遗传性溶酶体疾病，伴有进行性神经变性。对病理生理学的了解不足以及缺乏血液诊断标志物是鼻咽癌和其他几种神经性溶酶体疾病治疗和管理的主要障碍。为了确定疾病严重程度的相关性，我们对 Balb/c Npc1−/− 小鼠的前哨器官、大脑、肝脏和脾脏进行了全基因组表达谱分析，相对于 Npc1+/- 在无症状阶段以及早期和晚期症状阶段。出乎意料的是，我们发现在所有三个器官中先天免疫基因均显着上调，其表达随年龄而变化。我们入围了一组 12 个分泌基因，这些基因的表达随着年龄的增长在大脑和肝脏中稳步增加，作为神经系统和/或肝脏疾病的潜在血浆相关性。十个是先天免疫基因，其中八个归因于溶酶体。已知有几种在其他溶酶体疾病（包括戈谢病、桑德霍夫病和 MPSIIIB）的小鼠模型的患病器官中升高。我们在 Npc1−/− 以及 Balb/c Npc1nmf164 小鼠（具有更接近人类疾病突变体的点突变）的血浆中验证了最佳候选溶菌酶，并显示其对新兴疗法的反应减少。我们通过多种功能测定（包括抑制细菌感染以及细胞分析和免疫组织化学）进一步确定了 Npc1−/− 小鼠先天免疫的提高。这些数据显示 Npc1 −/− 脾脏和肝脏中的中性粒细胞升高（在受损组织附近检测到大病灶）。我们的结果共同产生了一组溶酶体、分泌性先天免疫基因，这些基因有可能被开发为与溶酶体储存相关的神经系统疾病的泛或特异性血浆标记物，并且诊断是一个主要问题。此外，中性粒细胞在患病器官中的积累（迄今为止与鼻咽癌无关）表明它们在病理生理学和疾病恶化中的作用。
Niemann-Pick Type C (NPC) disease is a rare, genetic, lysosomal disorder with progressive neurodegeneration. Poor understanding of the pathophysiology and a lack of blood-based diagnostic markers are major hurdles in the treatment and management of NPC and several additional, neurological lysosomal disorders. To identify disease severity correlates, we undertook whole genome expression profiling of sentinel organs, brain, liver, and spleen of Balb/c Npc1−/− mice relative to Npc1+/− at an asymptomatic stage, as well as early- and late-symptomatic stages. Unexpectedly, we found prominent up regulation of innate immunity genes with age-dependent change in their expression, in all three organs. We shortlisted a set of 12 secretory genes whose expression steadily increased with age in both brain and liver, as potential plasma correlates of neurological and/or liver disease. Ten were innate immune genes with eight ascribed to lysosomes. Several are known to be elevated in diseased organs of murine models of other lysosomal diseases including Gaucher’s disease, Sandhoff disease and MPSIIIB. We validated the top candidate lysozyme, in the plasma of Npc1−/− as well as Balb/c Npc1nmf164 mice (bearing a point mutation closer to human disease mutants) and show its reduction in response to an emerging therapeutic. We further established elevation of innate immunity in Npc1−/− mice through multiple functional assays including inhibition of bacterial infection as well as cellular analysis and immunohistochemistry. These data revealed neutrophil elevation in the Npc1 −/− spleen and liver (where large foci were detected proximal to damaged tissue). Together our results yield a set of lysosomal, secretory innate immunity genes that have potential to be developed as pan or specific plasma markers for neurological diseases associated with lysosomal storage and where diagnosis is a major problem. Further, the accumulation of neutrophils in diseased organs (hitherto not associated with NPC) suggests their role in pathophysiology and disease exacerbation.
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影响因子：
64.8
作者：
Cote, Marceline;Misasi, John;Ren, Tao;Bruchez, Anna;Lee, Kyungae;Filone, Claire Marie;Hensley, Lisa;Li, Qi;Ory, Daniel;Chandran, Kartik;Cunningham, James
通讯作者：
Cunningham, James
影响因子：
3.1
作者：
De Windt, Aloys;Rai, Myriam;Laaksonen, Reijo
通讯作者：
Laaksonen, Reijo
影响因子：
13.5
作者：
Beltroy, EP;Richardson, JA;Dietschy, JM
通讯作者：
Dietschy, JM
DOI：
10.1093/jnen/64.4.323
发表时间：
2005-04-01
影响因子：
3.2
作者：
Li, H;Repa, JJ;Dietschy, JM
通讯作者：
Dietschy, JM
影响因子：
2.9
作者：
Liao, Guanghong;Wen, Zhining;Irizarry, Kristopher;Huang, Ying;Mitsouras, Katherine;Darmani, Mariam;Leon, Terry;Shi, Leming;Bi, Xiaoning
通讯作者：
Bi, Xiaoning