Natural allelic variation of the IL-21 receptor modulates ischemic stroke infarct volume.
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 articleSubject
BrainNeurons
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
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https://hdl.handle.net/10161/23264Published Version (Please cite this version)
10.1172/jci84491Publication 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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Show full item recordScholars@Duke
Han Kyu Lee
Assistant Research Professor in Molecular Genetics and Microbiology
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.
Douglas Alan Marchuk
James B. Duke Distinguished 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
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
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.
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