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Natural allelic variation of the IL-21 receptor modulates ischemic stroke infarct volume.

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Date
2016-08
Authors
Lee, Han Kyu
Keum, Sehoon
Sheng, Huaxin
Warner, David S
Lo, Donald C
Marchuk, Douglas A
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Abstract
Risk for ischemic stroke has a strong genetic basis, but heritable factors also contribute to the extent of damage after a stroke has occurred. We previously identified a locus on distal mouse chromosome 7 that contributes over 50% of the variation in postischemic cerebral infarct volume observed between inbred strains. Here, we used ancestral haplotype analysis to fine-map this locus to 12 candidate genes. The gene encoding the IL-21 receptor (Il21r) showed a marked difference in strain-specific transcription levels and coding variants in neonatal and adult cortical tissue. Collateral vessel connections were moderately reduced in Il21r-deficient mice, and cerebral infarct volume increased 2.3-fold, suggesting that Il21r modulates both collateral vessel anatomy and innate neuroprotection. In brain slice explants, oxygen deprivation (OD) activated apoptotic pathways and increased neuronal cell death in IL-21 receptor-deficient (IL-21R-deficient) mice compared with control animals. We determined that the neuroprotective effects of IL-21R arose from signaling through JAK/STAT pathways and upregulation of caspase 3. Thus, natural genetic variation in murine Il21r influences neuronal cell viability after ischemia by modulating receptor function and downstream signal transduction. The identification of neuroprotective genes based on naturally occurring allelic variations has the potential to inform the development of drug targets for ischemic stroke treatment.
Type
Journal article
Subject
Brain
Neurons
Animals
Mice, Inbred BALB C
Mice, Inbred NOD
Mice, Knockout
Mice
Brain Ischemia
Brain Infarction
Oxygen
Chromosome Mapping
Signal Transduction
Apoptosis
Cell Survival
Haplotypes
Lod Score
Phenotype
Polymorphism, Single Nucleotide
Alleles
Quantitative Trait Loci
Female
Male
Interleukin-21 Receptor alpha Subunit
Genetic Variation
Neuroprotection
Permalink
https://hdl.handle.net/10161/23264
Published Version (Please cite this version)
10.1172/jci84491
Publication Info
Lee, Han Kyu; Keum, Sehoon; Sheng, Huaxin; Warner, David S; Lo, Donald C; & Marchuk, Douglas A (2016). Natural allelic variation of the IL-21 receptor modulates ischemic stroke infarct volume. The Journal of clinical investigation, 126(8). pp. 2827-2838. 10.1172/jci84491. Retrieved from https://hdl.handle.net/10161/23264.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Lo

Donald Ching-Tze Lo

Associate Professor in Neurobiology
Dr. Lo's laboratory focuses on the translation of basic neuroscience research into the identification new drug candidates and targets for neuropsychiatric diseases including Alzheimer's disease, Huntington's disease, stroke, and glaucoma. In this context, the laboratory has developed a series of discovery technologies, based on high-content screening and chemical genetics, to drive towards the efficient identification of new neurological drug candidates with strong likelihood of clinical s
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.
Marchuk

Douglas Alan Marchuk

Professor of Molecular Genetics and Microbiology
Vascular Morphogenesis: A Human Genetics Approach Advances in our understanding of fundamental biological events can often be made by the analysis of defects manifested in inherited diseases. The genes responsible for these genetic syndromes often encode proteins that act at critical points of the pathways that control fundamental biological processes such as cell division, differentiation, and cell death. This approach has lead to the discovery of novel gene products and/or biochem
Sheng

Huaxin Sheng

Associate Professor in Anesthesiology
We have successfully developed various rodent models of brain and spinal cord injuries in our lab, such as focal cerebral ischemia, global cerebral ischemia, head trauma, subarachnoid hemorrhage, intracerebral hemorrhage, spinal cord ischemia and compression injury. We also established cardiac arrest and hemorrhagic shock models for studying multiple organ dysfunction.  Our current studies focus on two projects. One is to examine the efficacy of catalytic antioxidant in treating cerebral is
Warner

David Samuel Warner

Distinguished Distinguished Professor of Anesthesiology, in the School of Medicine
Humans may sustain a variety of forms of acute central nervous system injury including ischemia, trauma, vasospasm, and perinatal hypoxemia. The Multidisciplinary Neuroprotection Laboratories is dedicated to examining the pathophysiology of acute brain and spinal cord injury with particular reference to disease states managed in the perioperative or neurointensive care environments. Rodent recovery models of cerebral ischemia, traumatic brain injury, cardiopulmonary bypass, subarachnoid he
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.
Alphabetical list of authors with Scholars@Duke profiles.
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