Though the causes of ischemic stroke are often identified, the ~35% of patients without a known cause are labeled as "cryptogenic strokes." Since there are no current methods for identifying causes of cryptogenic strokes, our laboratory has used a molecular approach in an attempt to solve this problem. We have examined gene expression in whole blood using whole genome microarrays and shown specific gene expression profiles in whole blood of patients who have known causes of stroke due to cardioembolism due to paroxysmal atrial fibrillation (PAF), non-PAF cardioembolism and large vessel atherosclerosis. PAF often causes a blood clot in the heart that embolizes to brain to produce a stroke. However, by the time an EKG and/or Holter monitor are performed after the stroke, the heart rhythm has returned to normal with no evidence of PAF and the stroke is designated as "cryptogenic." In the following aims we test whether our gene expression profiles for known PAF causes of cardioembolic stroke will detect cryptogenic strokes caused by PAF cardioembolism. In addition, we will examine gene expression differences in women and men following strokes caused by PAF because women are at a significantly higher risk for PAF related stroke than men, and the biological reasons for this are not understood.
Aim #1. Predict which cryptogenic strokes are caused by PAF using qRT-PCR measurement of RNA levels of genes identified in our previous microarray studies of strokes caused by PAF.
Aim #2. Demonstrate the cryptogenic cortical strokes predicted to be caused by PAF in Aim #1 have in fact: (a) PAF on prolonged outpatient cardiac monitoring after the stroke;(b) or have PAF on repeated Holter monitoring after the stroke(c) or PAF on repeat EKGs after the stroke.
Aim #3. Determine the gene expression differences in women compared to men following cryptogenic strokes caused by PAF using the subjects proven to have PAF in Aim#2. significance. The first two aims will predict PAF causes of cryptogenic strokes and confirm these by cardiac monitoring.
The third aim will address molecular pathways that are different between women and men with PAF to begin identifying the biological factors associated with the increased risk of PAF related stroke in women. There are over 260,000 cryptogenic strokes/ year in the US which compares to 270,000 new breast cancer cases/ year and 50,000 new Parkinson's cases/year. Our data suggest that >50% of cryptogenic cortical strokes may be due to unrecognized cardioembolism and half of these would be due to PAF. If we could identify all of the PAF cardioembolic cryptogenic strokes, then these patients would be treated with coumadin, Dabigatran or other oral anti-coagulant instead of anti-platelet agents or nothing. This would prevent thousands of strokes per year and is equivalent to the number of strokes treated with tPA per year.

Public Health Relevance

This study will use gene expression profiles from blood of patients known to have ischemic cortical strokes due to paroxysmal atrial fibrillation (PAF) to predict which cryptogenic stroke patients have a PAF cause of their strokes. This novel approach has the capability of identifying PAF causes of cryptogenic strokes within days of the events and with early anticoagulation will prevent thousands of ischemic strokes per year. The study will also examine the immune and inflammatory factors that are different in PAF related stroke in women compared to men to search for factors associated with the increased risk of PAF related stroke in women.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS079153-01A1
Application #
8411031
Study Section
Special Emphasis Panel (ZRG1-BDCN-L (02))
Program Officer
Koenig, James I
Project Start
2012-09-01
Project End
2017-04-30
Budget Start
2012-09-01
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$561,068
Indirect Cost
$196,738
Name
University of California Davis
Department
Neurology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Dykstra-Aiello, Cheryl; Jickling, Glen C; Ander, Bradley P et al. (2016) Altered Expression of Long Noncoding RNAs in Blood After Ischemic Stroke and Proximity to Putative Stroke Risk Loci. Stroke 47:2896-2903
Jickling, Glen C; Sharp, Frank R (2015) Improving the translation of animal ischemic stroke studies to humans. Metab Brain Dis 30:461-7
Jickling, Glen C; Sharp, Frank R (2015) Biomarker panels in ischemic stroke. Stroke 46:915-20
Stamova, Boryana; Jickling, Glen C; Ander, Bradley P et al. (2014) Gene expression in peripheral immune cells following cardioembolic stroke is sexually dimorphic. PLoS One 9:e102550
Jickling, Glen C; Ander, Bradley P; Zhan, Xinhua et al. (2014) microRNA expression in peripheral blood cells following acute ischemic stroke and their predicted gene targets. PLoS One 9:e99283
Sharp, Frank R; Jickling, Glen C (2014) Modeling immunity and inflammation in stroke: differences between rodents and humans? Stroke 45:e179-80
Bai, Zhouxian; Stamova, Boryana; Xu, Huichun et al. (2014) Distinctive RNA expression profiles in blood associated with Alzheimer disease after accounting for white matter hyperintensities. Alzheimer Dis Assoc Disord 28:226-33
Sharp, Frank R; Jickling, Glen C (2013) Whole genome expression of cellular response to stroke. Stroke 44:S23-5
Jickling, Glen C; Ander, Bradley P; Stamova, Boryana et al. (2013) RNA in blood is altered prior to hemorrhagic transformation in ischemic stroke. Ann Neurol 74:232-40
Tian, Yingfang; Stamova, Boryana; Jickling, Glen C et al. (2012) Y chromosome gene expression in the blood of male patients with ischemic stroke compared with male controls. Gend Med 9:68-75.e3

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