Prediction of immunotherapy targets for chronic cerebral hypoperfusion by bioinformatics method_Journal of Biomedical Engineering

Authors：

 ZHAO Mei ¹ , XUE Yanpeng ^2,3,4 , TIAN Qingqing ^2,3,4 , YANG He ^2,3,4 , JIANG Qing ^2,3,4 , YU Mengfan ^2,3,4 ,  CHEN Xin ^2,3,4

1. Department of Pharmacy, Sanya Central Hospital (The Third People’s Hospital of Hainan Province), Sanya, Hainan 572000, P. R. China;
2. Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin 150001, P. R. China;
3. Key Colleges and Universities Laboratory of Neurosurgery in Heilongjiang Province, Harbin 150001, P. R. China;
4. Institute of Neuroscience, Sino-Russian Medical Research Center, Harbin Medical University, Harbin 150001, P. R. China;

Corresponding author：

ZHAO Mei, Email: hrb_xiaozhaomei@163.com; CHEN Xin, Email: chenxin_tracy@hrbmu.edu.cn

Keywords：

Chronic cerebral hypoperfusion; Immunotherapy; Bioinformatics

DOI：

10.7507/1001-5515.202409037

Video：

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Chronic cerebral hypoperfusion (CCH) plays an important role in the occurrence and development of vascular dementia (VD). Recent studies have indicated that multiple stages of immune-inflammatory response are involved in the process of cerebral ischemia, drawing increasing attention to immune therapies for cerebral ischemia. This study aims to identify potential immune therapeutic targets for CCH using bioinformatics methods from an immunological perspective. We identified a total of 823 differentially expressed genes associated with CCH, and further screened for 9 core immune-related genes, namely RASGRP1, FGF12, SEMA7A, PAK6, EDN3, BPHL, FCGRT, HSPA1B and MLNR. Gene enrichment analysis showed that core genes were mainly involved in biological functions such as cell growth, neural projection extension, and mesenchymal stem cell migration. Biological signaling pathway analysis indicated that core genes were mainly involved in the regulation of T cell receptor, Ras and MAPK signaling pathways. Through LASSO regression, we identified RASGRP1 and BPHL as key immune-related core genes. Additionally, by integrating differential miRNAs and the miRwalk database, we identified miR-216b-5p as a key immune-related miRNA that regulates RASGRP1. In summary, the predicted miR-216b-5p/RASGRP1 signaling pathway plays a significant role in immune regulation during CCH, which may provide new targets for immune therapy in CCH.

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2.	Salminen A. Hypoperfusion is a potential inducer of immunosuppressive network in Alzheimer's disease. Neurochem Int, 2021, 142: 104919.
3.	Mao M, Xu Y, Zhang X Y, et al. MicroRNA-195 prevents hippocampal microglial/macrophage polarization towards the M1 phenotype induced by chronic brain hypoperfusion through regulating CX3CL1/CX3CR1 signaling. J Neuroinflammation, 2020, 17(1): 244.
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5.	Chen X, Holtzman D M. Emerging roles of innate and adaptive immunity in Alzheimer’s disease. Immunity, 2022, 55(12): 2236-2254.
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7.	Kim M, Kim B, Kim J I, et al. Mumefural improves recognition memory and alters ERK-CREB-BDNF signaling in a mouse model of chronic cerebral hypoperfusion. Nutrients, 2023, 15(14): 3271.
8.	Warde-Farley D, Donaldson S L, Comes O, et al. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res, 2010, 38: W214-W220.
9.	Hainsworth A H, Allan S M, Boltze J, et al. Translational models for vascular cognitive impairment: a review including larger species. BMC Med, 2017, 15(1): 16.
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13.	Lee J, Lee J, Song M, et al. NXP031 improves cognitive impairment in a chronic cerebral hypoperfusion-induced vascular dementia rat model through Nrf2 Signaling. Int J Mol Sci, 2021, 22(12): 6285.
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20.	Poh L, Fann D Y, Wong P, et al. AIM2 inflammasome mediates hallmark neuropathological alterations and cognitive impairment in a mouse model of vascular dementia. Mol Psychiatry, 2021, 26(8): 4544-4560.
21.	Zhang Z, Guo Z, Jin P, et al. Transcriptome profiling of hippocampus after cerebral hypoperfusion in mice. J Mol Neurosci, 2023, 73(6): 423-436.
22.	Li K, Du Y, Li L, et al. Bioinformatics approaches for anti-cancer drug discovery. Curr Drug Targets, 2020, 21(1): 3-17.
23.	Kortum R L, Rouquette-Jazdanian A K, Samelson L E. Ras and extracellular signal-regulated kinase signaling in thymocytes and T cells. Trends Immunol, 2013, 34(6): 259-268.
24.	Li S, Zhou B, Xue M, et al. Macrophage-specific FGF12 promotes liver fibrosis progression in mice. Hepatology, 2023, 77(3): 816-833.
25.	Deng J, Xu T, Yang J, et al. Sema7A, a brain immune regulator, regulates seizure activity in PTZ-kindled epileptic rats. CNS Neurosci Ther, 2020, 26(1): 101-116.
26.	Somekh I, Marquardt B, Liu Y, et al. Correction to: novel mutations in RASGRP1 are associated with immunodeficiency, immune dysregulation, and EBV-induced lymphoma. Clin Immunol, 2018, 38(6): 711.
27.	Baars M J D, Douma T, Simeonov D R, et al. Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity. Eur J Immunol, 2021, 51(2): 471-482.
28.	Pierret P, Vallée A, Mechawar N, et al. Cellular and subcellular localization of Ras guanyl nucleotide-releasing protein in the rat hippocampus. Neuroscience, 2001, 108(3): 381-390.
29.	Felix T F, Lopez Lapa R M, de Carvalho M, et al. MicroRNA modulated networks of adaptive and innate immune response in pancreatic ductal adenocarcinoma. PLoS One, 2019, 14(5): e0217421.
30.	Qi Y, Lai Y L, Shen P C, et al. Identification and validation of a miRNA-based prognostic signature for cervical cancer through an integrated bioinformatics approach. Sci Rep, 2020, 10(1): 22270.

1. Jonker M, Nooij F J. The internal image-like anti-idiotypic response to a CD3-specific monoclonal antibody in primates is dependent on the T cell-binding properties of the injected antibody. Eur J Immunol, 1987, 17(10): 1519-1522.
2. Salminen A. Hypoperfusion is a potential inducer of immunosuppressive network in Alzheimer's disease. Neurochem Int, 2021, 142: 104919.
3. Mao M, Xu Y, Zhang X Y, et al. MicroRNA-195 prevents hippocampal microglial/macrophage polarization towards the M1 phenotype induced by chronic brain hypoperfusion through regulating CX3CL1/CX3CR1 signaling. J Neuroinflammation, 2020, 17(1): 244.
4. Li M, Meng N, Guo X, et al. Dl-3-n-butylphthalide promotes remyelination and suppresses inflammation by regulating AMPK/SIRT1 and STAT3/NF-κB signaling in chronic cerebral hypoperfusion. Front Aging Neurosci, 2020, 12: 137.
5. Chen X, Holtzman D M. Emerging roles of innate and adaptive immunity in Alzheimer’s disease. Immunity, 2022, 55(12): 2236-2254.
6. Tukacs V, Mittli D, Hunyadi-Gulyás É, et al. Chronic cerebral hypoperfusion-induced disturbed proteostasis of mitochondria and MAM is reflected in the CSF of rats by proteomic analysis. Mol Neurobiol, 2023, 60(6): 3158-3174.
7. Kim M, Kim B, Kim J I, et al. Mumefural improves recognition memory and alters ERK-CREB-BDNF signaling in a mouse model of chronic cerebral hypoperfusion. Nutrients, 2023, 15(14): 3271.
8. Warde-Farley D, Donaldson S L, Comes O, et al. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res, 2010, 38: W214-W220.
9. Hainsworth A H, Allan S M, Boltze J, et al. Translational models for vascular cognitive impairment: a review including larger species. BMC Med, 2017, 15(1): 16.
10. Chen Y, Liu Q, Liu J, et al. Revealing the modular similarities and differences among alzheimer’s disease, vascular dementia, and Parkinson’s disease in genomic networks. Neuromolecular Med, 2022, 24(2): 125-138.
11. Sun Z, Gao C, Gao D, et al. Reduction in pericyte coverage leads to blood–brain barrier dysfunction via endothelial transcytosis following chronic cerebral hypoperfusion. Fluids Barriers CNS, 2021, 18(1): 21.
12. Farkas E, Luiten P G M, Bari F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev, 2007, 54(1): 162-180.
13. Lee J, Lee J, Song M, et al. NXP031 improves cognitive impairment in a chronic cerebral hypoperfusion-induced vascular dementia rat model through Nrf2 Signaling. Int J Mol Sci, 2021, 22(12): 6285.
14. Qu C, Song H, Shen J, et al. Mfsd2a reverses spatial learning and memory impairment caused by chronic cerebral hypoperfusion via protection of the blood–brain barrier. Front Neurosci, 2020, 14: 461.
15. Procter T V, Williams A, Montagne A. Interplay between brain pericytes and endothelial cells in dementia. Am J Pathol, 2021, 191(11): 1917-1931.
16. Zhang D, Cao Y, Mu J, et al. Inflammatory biomarkers and cerebral small vessel disease: a community-based cohort study. Stroke Vasc Neurol, 2022, 7(4): 302-309.
17. Xu J J, Guo S, Xue R, et al. Adalimumab ameliorates memory impairments and neuroinflammation in chronic cerebral hypoperfusion rats. Aging (Albany NY), 2021, 13(10): 14001-14014.
18. Baik S H, Selvaraji S, Fann D Y, et al. Hippocampal transcriptome profiling reveals common disease pathways in chronic hypoperfusion and aging. Aging (Albany NY), 2021, 13(11): 14651-14674.
19. Wang Y H, Cheng C, Zuo X Z, et al. Inhibition of A2AR gene methylation alleviates white matter lesions in chronic cerebral hypoperfusion rats. Eur Rev Med Pharmacol Sci, 2022, 26(8): 2702-2711.
20. Poh L, Fann D Y, Wong P, et al. AIM2 inflammasome mediates hallmark neuropathological alterations and cognitive impairment in a mouse model of vascular dementia. Mol Psychiatry, 2021, 26(8): 4544-4560.
21. Zhang Z, Guo Z, Jin P, et al. Transcriptome profiling of hippocampus after cerebral hypoperfusion in mice. J Mol Neurosci, 2023, 73(6): 423-436.
22. Li K, Du Y, Li L, et al. Bioinformatics approaches for anti-cancer drug discovery. Curr Drug Targets, 2020, 21(1): 3-17.
23. Kortum R L, Rouquette-Jazdanian A K, Samelson L E. Ras and extracellular signal-regulated kinase signaling in thymocytes and T cells. Trends Immunol, 2013, 34(6): 259-268.
24. Li S, Zhou B, Xue M, et al. Macrophage-specific FGF12 promotes liver fibrosis progression in mice. Hepatology, 2023, 77(3): 816-833.
25. Deng J, Xu T, Yang J, et al. Sema7A, a brain immune regulator, regulates seizure activity in PTZ-kindled epileptic rats. CNS Neurosci Ther, 2020, 26(1): 101-116.
26. Somekh I, Marquardt B, Liu Y, et al. Correction to: novel mutations in RASGRP1 are associated with immunodeficiency, immune dysregulation, and EBV-induced lymphoma. Clin Immunol, 2018, 38(6): 711.
27. Baars M J D, Douma T, Simeonov D R, et al. Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity. Eur J Immunol, 2021, 51(2): 471-482.
28. Pierret P, Vallée A, Mechawar N, et al. Cellular and subcellular localization of Ras guanyl nucleotide-releasing protein in the rat hippocampus. Neuroscience, 2001, 108(3): 381-390.
29. Felix T F, Lopez Lapa R M, de Carvalho M, et al. MicroRNA modulated networks of adaptive and innate immune response in pancreatic ductal adenocarcinoma. PLoS One, 2019, 14(5): e0217421.
30. Qi Y, Lai Y L, Shen P C, et al. Identification and validation of a miRNA-based prognostic signature for cervical cancer through an integrated bioinformatics approach. Sci Rep, 2020, 10(1): 22270.

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