Reframing the Biological Basis of Neuroprotection Using Functional Genomics: Differentially Weighted, Time-Dependent Multifactor Pathogenesis of Human Ischemic Brain Damage
Background: Neuroprotection studies are generally unable to demonstrate efficacy in humans. Our specific hypothesis is that multiple pathophysiologic pathways, of variable importance, contribute to ischemic brain damage. As a corollary to this, we discuss the broad hypothesis that a multifaceted app...
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| Format: | Article |
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Frontiers Media S.A.
2018-06-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fneur.2018.00497/full |
| _version_ | 1828907739923873792 |
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| author | William A. Kofke Yue Ren John G. Augoustides Hongzhe Li Katherine Nathanson Robert Siman Qing Cheng Meng Weiming Bu Sukanya Yandrawatthana Guy Kositratna Cecilia Kim Joseph E. Bavaria |
| author_facet | William A. Kofke Yue Ren John G. Augoustides Hongzhe Li Katherine Nathanson Robert Siman Qing Cheng Meng Weiming Bu Sukanya Yandrawatthana Guy Kositratna Cecilia Kim Joseph E. Bavaria |
| author_sort | William A. Kofke |
| collection | DOAJ |
| description | Background: Neuroprotection studies are generally unable to demonstrate efficacy in humans. Our specific hypothesis is that multiple pathophysiologic pathways, of variable importance, contribute to ischemic brain damage. As a corollary to this, we discuss the broad hypothesis that a multifaceted approach will improve the probability of efficacious neuroprotection. But to properly test this hypothesis the nature and importance of the multiple contributing pathways needs elucidation. Our aim is to demonstrate, using functional genomics, in human cardiac surgery procedures associated with cerebral ischemia, that the pathogenesis of perioperative human ischemic brain damage involves the function of multiple variably weighted proteins involving several pathways. We then use these data and literature to develop a proposal for rational design of human neuroprotection protocols.Methods: Ninety-four patients undergoing deep hypothermic circulatory arrest (DHCA) and/or aortic valve replacement surgery had brain damage biomarkers, S100β and neurofilament H (NFH), assessed at baseline, 1 and 24 h post-cardiopulmonary bypass (CPB) with analysis for association with 92 single nucleotide polymorphisms (SNPs) (selected by co-author WAK) related to important proteins involved in pathogenesis of cerebral ischemia.Results: At the nominal significance level of 0.05, changes in S100β and in NFH at 1 and 24 h post-CPB were associated with multiple SNPs involving several prospectively determined pathophysiologic pathways, but were not individually significant after multiple comparison adjustments. Variable weights for the several evaluated SNPs are apparent on regression analysis and, notably, are dissimilar related to the two biomarkers and over time post CPB. Based on our step-wise regression model, at 1 h post-CPB, SOD2, SUMO4, and GP6 are related to relative change of NFH while TNF, CAPN10, NPPB, and SERPINE1 are related to the relative change of S100B. At 24 h post-CPB, ADRA2A, SELE, and BAX are related to the relative change of NFH while SLC4A7, HSPA1B, and FGA are related to S100B.Conclusions: In support of the proposed hypothesis, association SNP data suggest function of specific disparate proteins, as reflected by genetic variation, may be more important than others with variation at different post-insult times after human brain ischemia. Such information may support rational design of post-insult time-sensitive multifaceted neuroprotective therapies. |
| first_indexed | 2024-12-13T17:58:12Z |
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| language | English |
| last_indexed | 2024-12-13T17:58:12Z |
| publishDate | 2018-06-01 |
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| spelling | doaj.art-0e3905e2ab1c414daa4839295883e1572022-12-21T23:36:18ZengFrontiers Media S.A.Frontiers in Neurology1664-22952018-06-01910.3389/fneur.2018.00497325022Reframing the Biological Basis of Neuroprotection Using Functional Genomics: Differentially Weighted, Time-Dependent Multifactor Pathogenesis of Human Ischemic Brain DamageWilliam A. Kofke0Yue Ren1John G. Augoustides2Hongzhe Li3Katherine Nathanson4Robert Siman5Qing Cheng Meng6Weiming Bu7Sukanya Yandrawatthana8Guy Kositratna9Cecilia Kim10Joseph E. Bavaria11Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Medicine, Division of Translational Medicine and Human Genetics Abramson Cancer Center Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Neurosurgery, University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA, United StatesThe Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United StatesDepartment of Surgery, University of Pennsylvania, Philadelphia, PA, United StatesBackground: Neuroprotection studies are generally unable to demonstrate efficacy in humans. Our specific hypothesis is that multiple pathophysiologic pathways, of variable importance, contribute to ischemic brain damage. As a corollary to this, we discuss the broad hypothesis that a multifaceted approach will improve the probability of efficacious neuroprotection. But to properly test this hypothesis the nature and importance of the multiple contributing pathways needs elucidation. Our aim is to demonstrate, using functional genomics, in human cardiac surgery procedures associated with cerebral ischemia, that the pathogenesis of perioperative human ischemic brain damage involves the function of multiple variably weighted proteins involving several pathways. We then use these data and literature to develop a proposal for rational design of human neuroprotection protocols.Methods: Ninety-four patients undergoing deep hypothermic circulatory arrest (DHCA) and/or aortic valve replacement surgery had brain damage biomarkers, S100β and neurofilament H (NFH), assessed at baseline, 1 and 24 h post-cardiopulmonary bypass (CPB) with analysis for association with 92 single nucleotide polymorphisms (SNPs) (selected by co-author WAK) related to important proteins involved in pathogenesis of cerebral ischemia.Results: At the nominal significance level of 0.05, changes in S100β and in NFH at 1 and 24 h post-CPB were associated with multiple SNPs involving several prospectively determined pathophysiologic pathways, but were not individually significant after multiple comparison adjustments. Variable weights for the several evaluated SNPs are apparent on regression analysis and, notably, are dissimilar related to the two biomarkers and over time post CPB. Based on our step-wise regression model, at 1 h post-CPB, SOD2, SUMO4, and GP6 are related to relative change of NFH while TNF, CAPN10, NPPB, and SERPINE1 are related to the relative change of S100B. At 24 h post-CPB, ADRA2A, SELE, and BAX are related to the relative change of NFH while SLC4A7, HSPA1B, and FGA are related to S100B.Conclusions: In support of the proposed hypothesis, association SNP data suggest function of specific disparate proteins, as reflected by genetic variation, may be more important than others with variation at different post-insult times after human brain ischemia. Such information may support rational design of post-insult time-sensitive multifaceted neuroprotective therapies.https://www.frontiersin.org/article/10.3389/fneur.2018.00497/fullneuroprotectionfunctional genomicscerebral ischemiacardiac surgerycardiopulmonary bypassbiomarkers |
| spellingShingle | William A. Kofke Yue Ren John G. Augoustides Hongzhe Li Katherine Nathanson Robert Siman Qing Cheng Meng Weiming Bu Sukanya Yandrawatthana Guy Kositratna Cecilia Kim Joseph E. Bavaria Reframing the Biological Basis of Neuroprotection Using Functional Genomics: Differentially Weighted, Time-Dependent Multifactor Pathogenesis of Human Ischemic Brain Damage Frontiers in Neurology neuroprotection functional genomics cerebral ischemia cardiac surgery cardiopulmonary bypass biomarkers |
| title | Reframing the Biological Basis of Neuroprotection Using Functional Genomics: Differentially Weighted, Time-Dependent Multifactor Pathogenesis of Human Ischemic Brain Damage |
| title_full | Reframing the Biological Basis of Neuroprotection Using Functional Genomics: Differentially Weighted, Time-Dependent Multifactor Pathogenesis of Human Ischemic Brain Damage |
| title_fullStr | Reframing the Biological Basis of Neuroprotection Using Functional Genomics: Differentially Weighted, Time-Dependent Multifactor Pathogenesis of Human Ischemic Brain Damage |
| title_full_unstemmed | Reframing the Biological Basis of Neuroprotection Using Functional Genomics: Differentially Weighted, Time-Dependent Multifactor Pathogenesis of Human Ischemic Brain Damage |
| title_short | Reframing the Biological Basis of Neuroprotection Using Functional Genomics: Differentially Weighted, Time-Dependent Multifactor Pathogenesis of Human Ischemic Brain Damage |
| title_sort | reframing the biological basis of neuroprotection using functional genomics differentially weighted time dependent multifactor pathogenesis of human ischemic brain damage |
| topic | neuroprotection functional genomics cerebral ischemia cardiac surgery cardiopulmonary bypass biomarkers |
| url | https://www.frontiersin.org/article/10.3389/fneur.2018.00497/full |
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