Silent cerebral infarctions (SCI) occur in 22% of children with sickle cell disease (SCD) and are associated with decreased cognitive function. By definition, these children have MRI and pathologic evidence consistent with brain ischemia or infarction, without symptoms of overt stroke. As the etiology of SCI is unknown, we lack the means to identify children at risk for SCI, institute early therapy, or follow the success of therapy. The overall goal of this grant proposal is to identify diagnostic/prognostic plasma biomarkers of SCI in children ages 5-14 years with SCD. In our pilot studies, using a non-biased proteomic analysis of existing baseline plasma samples at enrollment in the Silent Infarct Transfusion (SIT) Trial from patients with or without SCI, we found differences in the protein profile and the presence of brain specific proteins in plasma of children with SCI. The SIT Trial represents a unique opportunity to: 1) extend these studies to serial plasma samples from study participants, which would be obtained as part of this proposal, but are not presently being obtained as part of the SIT Trial;2) optimize sample procurement for deep proteomic analysis;and 3) assess biomarkers for prognostic value and therapeutic efficacy. We hypothesize that serial plasma samples optimized for proteomic studies from children with SCD and treated for SCI will contain diagnostic/prognostic biomarkers of SCI and treatment efficacy. The significance of the proposed studies is that identification of circulating markers of SCI could allow early intervention in these children, validate the efficacy of current therapy and provide insight into the design of new therapies. This proposal draws on the unique resources of the ongoing SIT Trial, the large and well phenotyped plasma samples in the SIT Trial Biologic Respository and the NHLBI Cardiovascular Proteomics Center at Johns Hopkins.
In Specific Aim I, we will identify plasma biomarkers of SCI and evaluate differences in these biomarkers among 4 groups of patients: SCI patients randomly assigned to chronic transfusion (1) or standard care (2), patients without SCI (3), and patients with recent evidence of ischemic CNS injury (4), using state of the art, non-biased proteomic techniques (protein depletion, HPLC, ITRAQ and LC/MS/MS).
In Specific Aim II, we will validate the efficacy of these biomarkers in predicting SCI and therapeutic response, using a combination of traditional western blotting and the development of high throughput multiplex antibody arrays. It is anticipated that these studies will provide new insights into the development of SCI and stroke in SCD and possibly ischemic CNS injury in other susceptible populations. This project has the potential to identify the protein biomarkers for the protection and evaluation of new and progressive silent cerebral infarcts. The identification of such circulating markers of SCI could allow early intervention in children who develop these lesions, help validate the efficacy of current therapy and provide insight into the design of new therapies. While we are studying a selected population of patients with a single gene disorder who develop silent cerebral infarction early in life, these results may generalize to the very large group of older individuals who develop silent cerebral infarctions as a presumed multi-factorial disorder (e.g., atherosclerosis, hypertension, diabetes, migraine, infection, other systemic diseases and aging), often associated with adverse outcomes such as dementia. Thus, the results of these studies could have a great deal of significance for public health in a variety of populations.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091759-03
Application #
7761227
Study Section
Special Emphasis Panel (ZHL1-CSR-H (O1))
Program Officer
Luksenburg, Harvey
Project Start
2008-01-15
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
3
Fiscal Year
2010
Total Cost
$393,994
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Chaturvedi, Shruti; Bhatnagar, Pallav; Bean, Christopher J et al. (2017) Genome-wide association study to identify variants associated with acute severe vaso-occlusive pain in sickle cell anemia. Blood 130:686-688
Lance, Eboni I; Comi, Anne M; Johnston, Michael V et al. (2015) Risk Factors for Attention and Behavioral Issues in Pediatric Sickle Cell Disease. Clin Pediatr (Phila) 54:1087-93
Lance, Eboni I; Casella, James F; Everett, Allen D et al. (2014) Proteomic and biomarker studies and neurological complications of pediatric sickle cell disease. Proteomics Clin Appl 8:813-27
Bhatnagar, Pallav; Barron-Casella, Emily; Bean, Christopher J et al. (2013) Genome-wide meta-analysis of systolic blood pressure in children with sickle cell disease. PLoS One 8:e74193
Bhatnagar, Pallav; Keefer, Jeffrey R; Casella, James F et al. (2013) Association between baseline fetal hemoglobin levels and incidence of severe vaso-occlusive pain episodes in children with sickle cell anemia. Pediatr Blood Cancer 60:E125-7
Bean, Christopher J; Boulet, Sheree L; Yang, Genyan et al. (2013) Acute chest syndrome is associated with single nucleotide polymorphism-defined beta globin cluster haplotype in children with sickle cell anaemia. Br J Haematol 163:268-76
Faulcon, Lisa M; Fu, Zongming; Dulloor, Pratima et al. (2013) Thrombospondin-1 and L-selectin are associated with silent cerebral infarct in children with sickle cell anaemia. Br J Haematol 162:421-4
Jordan, Lori C; Casella, James F; DeBaun, Michael R (2012) Prospects for primary stroke prevention in children with sickle cell anaemia. Br J Haematol 157:14-25
Savage, William J; Barron-Casella, Emily; Fu, Zongming et al. (2011) Plasma glial fibrillary acidic protein levels in children with sickle cell disease. Am J Hematol 86:427-9
Bhatnagar, Pallav; Purvis, Shirley; Barron-Casella, Emily et al. (2011) Genome-wide association study identifies genetic variants influencing F-cell levels in sickle-cell patients. J Hum Genet 56:316-23

Showing the most recent 10 out of 14 publications