藉大數據挖掘和全基因組辨別經由系統生物學方法來探究各期哮喘的進展機制

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研究生：	吳瑞恩 Wu, Rui-En
論文名稱：	藉大數據挖掘和全基因組辨別經由系統生物學方法來探究各期哮喘的進展機制 nvestigating the Progressive Mechanism from Asthma of Each Stage by Big Data Mining and via Ge-nome-Wide Microarray Data Identification : System Biology Approach
指導教授：	陳博現 Chen, Bor-Sen
口試委員:	王禹超王慧菁汪宏達
學位類別：	碩士 Master
系所名稱：	電機資訊學院 - 通訊工程研究所 Communications Engineering
論文出版年：	2018
畢業學年度：	106
語文別：	英文
論文頁數：	75
中文關鍵詞：	哮喘、氣道高反應性、氣道炎症、免疫系統、系統鑑定方法、表觀遺傳修飾
外文關鍵詞：	Asthma, airway hyperresponsiveness, airway inflammation, immune system, system identification method, epigenetic modification
相關次數：	點閱：3 下載：0
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哮喘是一種導致全球健康問題的慢性呼吸道疾病。其特徵是氣道高反應性（AHR），氣道阻塞，肺和氣道炎症，其由免疫系統，突變，表觀遺傳和環境因素如過敏原和無機污染物之間的相互作用引起，使得疾病過於復雜。因此，我們通過大數據庫挖掘構建了人類細胞的候選全基因組 - 遺傳和表觀遺傳網絡（GWGENs），並通過系統識別方法和順序檢測方案修剪候選GWGEN中的假陽性，確定了三個哮喘階段的三個真實GWGEN。在下一步中，為了研究每個階段中重要的致病進展機制，我們通過原始網絡投影（PNP）方法從每個階段的實際GWGEN中提取相應的核心GWGEN。三個核心GWGEN被預測到KEGG途徑，以獲得哮喘每個階段的核心途徑，以研究相應的致病機制。根據研究結果，我們推測起始哮喘發作的原因可能是通過微環境（LPS，香煙煙霧），基因突變和表觀遺傳修改導致較低的先天免疫，哮喘易感性和的內皮屏障恢復減少。當哮喘進展到第二階段時，我們推測哮喘患者由於T細胞分化為T輔助2型導致炎症而導致肺和氣道損傷，並且導致氣道阻塞以及由支氣管增生引起的AHR平滑肌肉細胞和平滑的肌肉收縮。此外，T細胞紊亂，肺和氣道損傷以及氣道通透性增加可能導致哮喘進入最後階段。在哮喘的最後階段，我們推測哮喘患者由於T細胞分化為1型T輔助細胞而分泌粘液，氣道和肺部炎症而導致氣道阻塞。此外，氣道重塑可能導致氣道纖維化和氣道狹窄。最後症狀可能導致氣道對微環境的更大易感性。
最後，通過藥物靶標數據庫的挖掘，連接圖譜（Cmap），我們確定了一些基於致病機制的重要生物標誌物作為哮喘治療中多分子藥物設計的各階段哮喘的藥物靶標。提供1327種不同藥物中14,207種基因的微陣列數據。根據藥物靶標的重要致病機制，我們設計了多種分子藥物（地塞米松，tomatidine，木犀草素），以恢復那些藥物靶基因的細胞功能障礙。

Asthma is a chronic respiratory disease that leads to worldwide health problem. It is characterized by airway hyperresponsiveness (AHR), airway obstruction, lung and airway inflammation, which are caused by the interactions between the immune system, mutation, epigenetic and environmental factors such as allergens and inorganic pollutants making the disease too complicated. Therefore, we constructed the candidate genome-wide-genetic and epigenetic networks (GWGENs) of human cells by big database mining and identified the three real GWGENs of three stages of asthma by pruning false-positives in candidate GWGENs through system identifica-tion method and system order detection scheme. In the next step, in order to investi-gate the significant pathogenic progression mechanisms in each stage, we extracted the corresponding core GWGENs from real GWGENs in each stage through the prin-cipal network projection (PNP) method. Three core GWGENs are projected to KEGG pathways to attain core pathways in each stage of asthma to investigate the corre-sponding pathogenic mechanism. According to the results of the study, we speculated that the cause of the beginning asthma attacking may be due to lower innate immunity, asthma susceptibility and the reduced endothelial barrier recovery through the micro-environment (LPS, cigarette smoke), genetic mutation and epigenetic modification. When asthma progressed to the second stage, we speculated that the asthma patient suffered to the lung and airway injure due to differentiation of T cells into T helper type 2 causing inflammation and the next symptoms caused airway obstruction and AHR that was caused by proliferated bronchial smooth muscle cell and smooth mus-cle contraction. Moreover, disordered T cell, lung and airway injury and increased airway permeability could cause asthma to the final stage. In the final stage of asthma, we speculated that the asthma patient suffer airway obstruction due to secreted mucus,
airway and lung inflammation due to differentiation of T cells into type 1 T helper. Moreover, airway remodeling could cause to airway fibrosis and airway narrowing. Finally symptoms could cause more susceptibility with airway to microenvironment.
At last, we identify some significant biomarkers based on pathogenic mechanism as drug targets of each stage Asthma for multiple molecular drug design in the thera-peutic treatment of Asthma, via the mining of the drug- target database, Connectivity Map (Cmap) that could provide the microarray data of 14,207 genes in 1,327 different drugs. According to the drug targets based the important pathogenic mechanisms, we design multiple molecular drugs (dexamethasone, tomatidine, luteolin) to restore the cellular dysfunctions of those drug target gene.

致謝    I
中文摘要    II
ABSTRACT    III
CONTENTS    V
CHAPTER 1  INTRODUCTION    1
CHAPTER 2  RESULTS    5
2.1 THE IDENTIFIED GWGENS, CORE GWGENS AND THEIR CORRESPONDING CORE PATHWAYS IN EACH STAGE OF ASTHMA    5
2.2 CORE PATHWAYS OF QUIET STAGE ASTHMA    6
2.3 CORE PATHWAYS OF EXACERBATION STAGE OF ASTHMA    8
2.4 CORE PATHWAYS OF FOLLOW-UP STAGE OF ASTHMA    11
CHAPTER 3  DISCUSSION    14
3.1 THE MAIN PATHOGENIC PROGRESSION MECHANISM OF QUIET STAGE OF ASTHMA    14
3.2 THE PATHOGENIC PROGRESSION MECHANISM OF EXACERBATION STAGE OF ASTHMA    17
3.3 THE PATHOGENIC PROGRESSION MECHANISM OF FOLLOW-UP STAGE OF ASTHMA    21
3.4 THE OVERALL PROGRESSION MECHANISM TO ASTHMA FOR DRUG TARGETS IDENTIFICATION AND MULTIPLE MOLECULE DRUGS DESIGN FOR EACH STAGE    23
CHAPTER 4  CONCLUSION    27
CHAPTER 5  MATERIALS AND METHODS    29
5.1 OVERVIEW OF THE CONSTRUCTION PROCESSES OF REAL GWGENS OF EACH STAGES PROGRESSION OF ASTHMA    29
5.2 BIG DATA MINING AND PREPROCESSING OF ASTHMA DATA    30
5.3 CONSTRUCTING STOCHASTIC SYSTEM MODELS OF PPIN AND GRN OF CANDIDATE GWGEN FOR ASTHMA OF EACH STAGE    31
5.4 PARAMETER ESTIMATION OF GWGENS BY MICROARRAY DATA AND SYSTEM IDENTIFICATION METHOD    34
5.5 EXTRACTING CORE NETWORK FROM THE REAL GWGEN BY USING THE PNP
METHOD    44
TABLES    47
TABLE 1. THE NUMBERS OF NODES IN CANDIDATE, QUIET, EXACERBATION AND FOLLOW-UP STAGES OF GWGENS:    47
TABLE 2. THE NUMBER OF EDGES OF GWGENS IN CANDIDATE, QUIET, EXACERBATION AND FOLLOW-UP STAGES OF ASTHMA:    48
TABLE 3. THE SPECIFIC CELLULAR FUNCTIONS AND RELATED PATHWAYS OF TARGET GENES IN THE ASTHMA OF QUIET STAGE BY APPLYING THE DAVID ANALYSIS.    49
TABLE 4. THE SPECIFIC CELLULAR FUNCTIONS AND RELATED PATHWAYS IN THE ASTHMA OF EXACERBATION STAGE BY APPLYING THE DAVID ANALYSIS.    50
TABLE 5. THE SPECIFIC CELLULAR FUNCTIONS AND RELATED PATHWAYS IN THE ASTHMA OF FOLLOW-UP STAGE BY APPLYING THE DAVID ANALYSIS    51
TABLE 6. DESIGN OF MULTIPLE MOLECULES DRUG TO DRUG TARGET GENES FOR ASTHMA IN THE QUIET STAGE. + DENOTES ACTIVATION, - DENOTES INACTIVATION AND 0 DENOTES NO EFFECT.    52
TABLE 7. DESIGN OF MULTIPLE MOLECULES DRUG TO DRUG TARGET GENES FOR ASTHMA IN THE EXACERBATION STAGE. + DENOTES ACTIVATION, - DENOTES INACTIVATION AND 0 DENOTES NO EFFECT.    53
TABLE 8. DESIGN OF MULTIPLE MOLECULES DRUG TO DRUG TARGET GENES FOR ASTHMA IN THE FOLLOW-UP STAGE.    54
FIGURES    55
FIGURE 1. THE FLOW CHART OF CONSTRUCTING GWGENS TO INVESTIGATE THE PATHOGENIC PROGRESSION MECHANISM OF ASTHMA FOR THE IDENTIFICATION OF MULTIPLE DRUG TARGETS AND THE DISCOVERY OF POTENTIAL MULTI-MOLECULE DRUGS VIA SYSTEMS BIOLOGY APPROACH.    56
FIGURE 2. THE GWGEN OF QUIET STAGE ASTHMA.    57
FIGURE 3. THE GWGEN OF EXACERBATION STAGE ASTHMA.    58
FIGURE 4. THE GWGEN OF FOLLOW-UP STAGE ASTHMA.    59
FIGURE 5. THE CORE GWGEN OF QUIET STAGE ASTHMA.    60
FIGURE 6. THE CORE GWGEN OF EXACERBATION STAGE ASTHMA.    61
FIGURE 7. THE CORE GWGEN OF FOLLOW-UP STAGE ASTHMA    62
FIGURE 8. THE PATHOGENIC MECHANISM OF CORE PATHWAYS OF QUIET STAGE ASTHMA    63
FIGURE 9. THE PATHOGENIC MECHANISM OF CORE PATHWAYS OF EXACERBATION STAGE ASTHMA.    64
FIGURE 10. THE PATHOGENIC MECHANISM OF CORE PATHWAYS OF FOLLOW-UP STAGE ASTHMA    66
FIGURE 11. THE OVERALL PATHOGENIC PROGRESSION MECHANISM OF ASTHMA    68
REFERENCES    70
                                

1. Nunes, C., A.M. Pereira, and M. Morais-Almeida, Asthma costs and social impact. Asthma Res Pract, 2017. 3: p. 1.
2. Handy, D.E., R. Castro, and J. Loscalzo, Epigenetic modifications: basic mechanisms and role in cardiovascular disease. Circulation, 2011. 123(19): p. 2145-56.
3. Maltby, S., et al., Targeting MicroRNA Function in Respiratory Diseases: Mini-Review. Front Physiol, 2016. 7: p. 21.
4. Tessier, L., et al., Impaired response of the bronchial epithelium to inflammation characterizes severe equine asthma. BMC Genomics, 2017. 18(1): p. 708.
5. Vasu, V.T., C.E. Cross, and K. Gohil, Nr1d1, an important circadian pathway regulatory gene, is suppressed by cigarette smoke in murine lungs. Integr Cancer Ther, 2009. 8(4): p. 321-8.
6. Kazi, J.U. and L. Ronnstrand, FLT3 signals via the adapter protein Grb10 and overexpression of Grb10 leads to aberrant cell proliferation in acute myeloid leukemia. Mol Oncol, 2013. 7(3): p. 402-18.
7. Warren, K.J., et al., The TORC1-activated Proteins, p70S6K and GRB10, Regulate IL-4 Signaling and M2 Macrophage Polarization by Modulating Phosphorylation of Insulin Receptor Substrate-2. J Biol Chem, 2016. 291(48): p. 24922-24930.
8. Sun, Z., Y.E. Chin, and D.D. Zhang, Acetylation of Nrf2 by p300/CBP augments promoter-specific DNA binding of Nrf2 during the antioxidant response. Mol Cell Biol, 2009. 29(10): p. 2658-72.
9. Schembri, F., et al., MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium. Proc Natl Acad Sci U S A, 2009. 106(7): p. 2319-24.
10. Yang, I.V., et al., The clinical and environmental determinants of airway transcriptional profiles in allergic asthma. Am J Respir Crit Care Med, 2012. 185(6): p. 620-7.
11. Liu, Q., et al., Cutting Edge: Synchronization of IRF1, JunB, and C/EBPbeta Activities during TLR3-TLR7 Cross-Talk Orchestrates Timely Cytokine Synergy in the Proinflammatory Response. J Immunol, 2015. 195(3): p. 801-5.
12. Szczeklik, A., R. Pieton, and J. Sieradzki, Alternation in both insulin release and its hypoglycemic effects in atopic bronchial asthma. J Allergy Clin Immunol, 1980. 66(5): p. 424-7.
13. Ji, H. and G.K. Khurana Hershey, Genetic and epigenetic influence on the response to environmental particulate matter. J Allergy Clin Immunol, 2012. 129(1): p. 33-41.
14. Gahring, L.C., et al., Nicotinic alpha 7 receptor expression and modulation of the lung epithelial response to lipopolysaccharide. PLoS One, 2017. 12(4): p. e0175367.
15. Breitling, L.P., et al., Tobacco-smoking-related differential DNA methylation: 27K discovery and replication. Am J Hum Genet, 2011. 88(4): p. 450-7.
16. Afroz, S., et al., A Comprehensive Gene Expression Meta-analysis Identifies Novel Immune Signatures in Rheumatoid Arthritis Patients. Front Immunol, 2017. 8: p. 74.
17. Chogtu, B., D. Bhattacharjee, and R. Magazine, Epigenetics: The New Frontier in the Landscape of Asthma. Scientifica (Cairo), 2016. 2016: p. 4638949.
18. Noguchi, E., et al., Positional identification of an asthma susceptibility gene on human chromosome 5q33. Am J Respir Crit Care Med, 2005. 172(2): p. 183-8.
19. Kwak, H.J., et al., The Wnt/beta-catenin signaling pathway regulates the development of airway remodeling in patients with asthma. Exp Mol Med, 2015. 47: p. e198.
20. Han, Z., et al., Pyruvate dehydrogenase complex deficiency caused by ubiquitination and proteasome-mediated degradation of the E1 subunit. J Biol Chem, 2008. 283(1): p. 237-43.
21. Amiot, L., N. Vu, and M. Samson, Immunomodulatory properties of HLA-G in infectious diseases. J Immunol Res, 2014. 2014: p. 298569.
22. Philibert, R.A., et al., Coordinated DNA methylation and gene expression changes in smoker alveolar macrophages: specific effects on VEGF receptor 1 expression. J Leukoc Biol, 2012. 92(3): p. 621-31.
23. Hunninghake, G.M., et al., MMP12, lung function, and COPD in high-risk populations. N Engl J Med, 2009. 361(27): p. 2599-608.
24. Philibert, R.A., et al., The effect of smoking on MAOA promoter methylation in DNA prepared from lymphoblasts and whole blood. Am J Med Genet B Neuropsychiatr Genet, 2010. 153B(2): p. 619-628.
25. Marcos-Ramiro, B., et al., RhoB controls endothelial barrier recovery by inhibiting Rac1 trafficking to the cell border. J Cell Biol, 2016. 213(3): p. 385-402.
26. Pejanovic, N., et al., Regulation of nuclear factor kappaB (NF-kappaB) transcriptional activity via p65 acetylation by the chaperonin containing TCP1 (CCT). PLoS One, 2012. 7(7): p. e42020.
27. Frazao, J.B., et al., Regulation of CYBB Gene Expression in Human Phagocytes by a Distant Upstream NF-kappaB Binding Site. J Cell Biochem, 2015. 116(9): p. 2008-17.
28. Song, S.M., et al., Identification of a Novel Mutation in the CYBB Gene, p.Asp378Gly, in a Patient With X-linked Chronic Granulomatous Disease. Allergy Asthma Immunol Res, 2014. 6(4): p. 366-9.
29. Dzeja, P. and A. Terzic, Adenylate kinase and AMP signaling networks: metabolic monitoring, signal communication and body energy sensing. Int J Mol Sci, 2009. 10(4): p. 1729-72.
30. Foreman, H.C.C., et al., P021 Activation of interferon regulatory factor 5 in innate immune signaling by site specific phosphorylation. Cytokine, 2012. 59(3): p. 525.
31. Byrne, A.J., et al., A critical role for IRF5 in regulating allergic airway inflammation. Mucosal Immunol, 2017. 10(3): p. 716-726.
32. Cao, D., et al., MicroRNA-196b promotes cell proliferation and suppress cell differentiation in vitro. Biochem Biophys Res Commun, 2015. 457(1): p. 1-6.
33. Mahn, K., et al., Ca(2+) homeostasis and structural and functional remodelling of airway smooth muscle in asthma. Thorax, 2010. 65(6): p. 547-52.
34. Qi, Y., et al., Human basophils express amphiregulin in response to T cell-derived IL-3. J Allergy Clin Immunol, 2010. 126(6): p. 1260-6 e4.
35. Ray, A. and L. Cohn, Th2 cells and GATA-3 in asthma: new insights into the regulation of airway inflammation. Journal of Clinical Investigation, 1999. 104(8): p. 985-993.
36. Shi, Y., et al., A Liver-X-Receptor Ligand, T0901317, Attenuates IgE Production and Airway Remodeling in Chronic Asthma Model of Mice. PLoS ONE, 2014. 9(3): p. e92668.
37. Jose, C.C., et al., Nickel exposure induces persistent mesenchymal phenotype in human lung epithelial cells through epigenetic activation of ZEB1. Mol Carcinog, 2018. 57(6): p. 794-806.
38. Karpurapu, M., et al., Kruppel like factor 4 promoter undergoes active demethylation during monocyte/macrophage differentiation. PLoS One, 2014. 9(4): p. e93362.
39. de Kouchkovsky, D.A., S. Ghosh, and C.V. Rothlin, Negative Regulation of Type 2 Immunity. Trends in immunology, 2017. 38(3): p. 154-167.
40. Liu, C.H., et al., miR-21 and KLF4 jointly augment epithelialmesenchymal transition via the Akt/ERK1/2 pathway. Int J Oncol, 2017. 50(4): p. 1109-1115.
41. Ayada, C., et al., Angiotensinogen gene M235T and angiotensin II-type 1 receptor gene A/C1166 polymorphisms in chronic obtructive pulmonary disease. International Journal of Clinical and Experimental Medicine, 2015. 8(3): p. 4521-4526.
42. Torgerson, D.G., et al., Resequencing candidate genes implicates rare variants in asthma susceptibility. Am J Hum Genet, 2012. 90(2): p. 273-81.
43. Himes, B.E., et al., Vitamin D Modulates Expression of the Airway Smooth Muscle Transcriptome in Fatal Asthma. PLoS One, 2015. 10(7): p. e0134057.
44. Das, D., et al., Major vault protein regulates cell growth/survival signaling through oxidative modifications. Cell Signal, 2016. 28(1): p. 12-8.
45. Kedracka-Krok, S., et al., Proteomic analysis of proton beam irradiated human melanoma cells. PLoS One, 2014. 9(1): p. e84621.
46. Moustakas, A. and C.-H. Heldin, Mechanisms of TGFβ-Induced Epithelial–Mesenchymal Transition. Journal of Clinical Medicine, 2016. 5(7): p. 63.
47. Iyer, S.S. and G. Cheng, Role of Interleukin 10 Transcriptional Regulation in Inflammation and Autoimmune Disease. Critical reviews in immunology, 2012. 32(1): p. 23-63.
48. Chung, F., Anti-inflammatory cytokines in asthma and allergy: interleukin-10, interleukin-12, interferon-gamma. Mediators Inflamm, 2001. 10(2): p. 51-9.
49. Prunicki, M., et al., Exposure to NO2, CO, and PM2.5 is linked to regional DNA methylation differences in asthma. Clin Epigenetics, 2018. 10: p. 2.
50. Kim, H.Y., D.T. Umetsu, and R.H. Dekruyff, Innate lymphoid cells in asthma: Will they take your breath away? Eur J Immunol, 2016. 46(4): p. 795-806.
51. Begin, P. and K.C. Nadeau, Epigenetic regulation of asthma and allergic disease. Allergy Asthma Clin Immunol, 2014. 10(1): p. 27.
52. Ethier, M.F., E. Cappelluti, and J.M. Madison, Mechanisms of interleukin-4 effects on calcium signaling in airway smooth muscle cells. J Pharmacol Exp Ther, 2005. 313(1): p. 127-33.
53. Sadeghnejad, A., et al., IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood, a longitudinal study. Respir Res, 2008. 9: p. 2.
54. Song, Y. and Z. Yan, Exploring of the molecular mechanism of rhinitis via bioinformatics methods. Mol Med Rep, 2018. 17(2): p. 3014-3020.
55. Magi, R., et al., Genome-wide association analysis of imputed rare variants: application to seven common complex diseases. Genet Epidemiol, 2012. 36(8): p. 785-96.
56. Salamon, P., et al., The Involvement of Protein Kinase D in T Cell-Induced Mast Cell Activation. Int Arch Allergy Immunol, 2016. 171(3-4): p. 203-208.
57. Uhm, T.G., B.S. Kim, and I.Y. Chung, Eosinophil development, regulation of eosinophil-specific genes, and role of eosinophils in the pathogenesis of asthma. Allergy Asthma Immunol Res, 2012. 4(2): p. 68-79.
58. Rutkowski, K., et al., Allergic diseases: the price of civilisational progress. Advances in Dermatology and Allergology/Postȩpy Dermatologii i Alergologii, 2014. 31(2): p. 77-83.
59. Hansel, T.T., et al., A Comprehensive Evaluation of Nasal and Bronchial Cytokines and Chemokines Following Experimental Rhinovirus Infection in Allergic Asthma: Increased Interferons (IFN-gamma and IFN-lambda) and Type 2 Inflammation (IL-5 and IL-13). EBioMedicine, 2017. 19: p. 128-138.
60. Miyagaki, T., et al., Eotaxins and CCR3 interaction regulates the Th2 environment of cutaneous T-cell lymphoma. J Invest Dermatol, 2010. 130(9): p. 2304-11.
61. Dai, C., et al., A CCL24-dependent pathway augments eosinophilic airway inflammation in house dust mite-challenged Cd163(-/-) mice. Mucosal Immunol, 2016. 9(3): p. 702-17.
62. Uematsu, S., et al., Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells. Nat Immunol, 2006. 7(8): p. 868-74.
63. Williams, J.W., et al., Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation. Nat Commun, 2013. 4: p. 2990.
64. Cui, J., et al., USP3 inhibits type I interferon signaling by deubiquitinating RIG-I-like receptors. Cell Res, 2014. 24(4): p. 400-16.
65. Li, Q., et al., MicroRNA-224 is upregulated in HepG2 cells and involved in cellular migration and invasion. J Gastroenterol Hepatol, 2010. 25(1): p. 164-71.
66. Lu, T.X., A. Munitz, and M.E. Rothenberg, MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression(). Journal of immunology (Baltimore, Md. : 1950), 2009. 182(8): p. 4994-5002.
67. Wright, W.R., et al., Inflammatory Transcriptome Profiling of Human Monocytes Exposed Acutely to Cigarette Smoke. PLoS ONE, 2012. 7(2): p. e30120.
68. Girkin, J., et al., CCL7 and IRF-7 Mediate Hallmark Inflammatory and IFN Responses following Rhinovirus 1B Infection. J Immunol, 2015. 194(10): p. 4924-30.
69. Collin, M., R. Dickinson, and V. Bigley, Haematopoietic and immune defects associated with GATA2 mutation. Br J Haematol, 2015. 169(2): p. 173-87.
70. Harris, K.M., A. Fasano, and D.L. Mann, Monocytes differentiated with IL-15 support Th17 and Th1 responses to wheat gliadin: implications for celiac disease. Clin Immunol, 2010. 135(3): p. 430-9.
71. Zepp, J.A., et al., TRAF4 restricts IL-17-mediated pathology and signaling processes. Journal of immunology (Baltimore, Md. : 1950), 2012. 189(1): p. 33-37.
72. Song, T.T., et al., Systemic pro-inflammatory response facilitates the development of cerebral edema during short hypoxia. J Neuroinflammation, 2016. 13(1): p. 63.
73. Atochina-Vasserman, E.N., et al., Early alveolar epithelial dysfunction promotes lung inflammation in a mouse model of Hermansky-Pudlak syndrome. Am J Respir Crit Care Med, 2011. 184(4): p. 449-58.
74. Yu, C.R., et al., Suppressor of cytokine signaling 3 regulates proliferation and activation of T-helper cells. J Biol Chem, 2003. 278(32): p. 29752-9.
75. Schuliga, M., NF-kappaB Signaling in Chronic Inflammatory Airway Disease. Biomolecules, 2015. 5(3): p. 1266-83.
76. Baud, V. and D. Collares, Post-Translational Modifications of RelB NF-kappaB Subunit and Associated Functions. Cells, 2016. 5(2).
77. Roy, P., et al., Non-canonical NFkappaB mutations reinforce pro-survival TNF response in multiple myeloma through an autoregulatory RelB:p50 NFkappaB pathway. Oncogene, 2017. 36(10): p. 1417-1429.
78. Ookawa, K., et al., Transcriptional activation of the MUC2 gene by p53. J Biol Chem, 2002. 277(50): p. 48270-5.
79. O'Connell D Fau - O'Connell, D., et al., IFN-γ-induced JAK/STAT, but not NF-κB, signaling pathway is insensitive to glucocorticoid in airway epithelial cells. (1040-0605 (Print)).
80. Chen, B.-S. and C.-C. Wu, Systems Biology as an Integrated Platform for Bioinformatics, Systems Synthetic Biology, and Systems Metabolic Engineering. Cells, 2013. 2(4): p. 635-688.

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