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Becker Lab

Summary:

The main focus of the Becker lab has been on the mechanisms and consequences of post-ischemic myocardial inflammation.

We have found that the acute inflammation accompanying myocardial infarction begins shortly after reperfusion and enlarges the area of irreversible injury. Limiting inflammation by various means, such as with antibodies or drugs, can reduce infarct size and improve left ventricular function. Inflammation begins with conversion of endothelial cells in the ischemic myocardium to a pro-inflammatory phenotype, with increased expression of leukocyte adhesion proteins, such as intercellular adhesion molecule-1 (ICAM-1), and microvascular trapping of neutrophils with accumulation in the myocardium.

ICAM-1 gene upregulation in the post-ischemic myocardium is mediated by tumor necrosis factor alpha (TNFalpha) through the NFkB pathway, but also by activation (phosphorylation) of the transcription factor Stat3, bound to the transcriptional activator Sp1. Stat3 is phosphorylated in turn by interaction with Rac1, an essential subunit of the endothelial NADPH oxidase, through a novel multiprotein complex involving Stat3, Rac1, and protein kinase C (PKC).

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Human Studies

  • FUNCTIONAL GENOMICS OF PLATELET AGGREGATION USING IPS AND DERIVED MEGAKARYOCYTES ( Human Study )

    The causal mechanisms of common diseases are only marginally illuminated by genetic variants found in genome wide association studies (GWAS) using single nucleotide polymorphism (SNPs). Platelet pathways reflecting hemostasis and thrombosis are the underlying substrate for many cardiovascular diseases and related acute events. To overcome GWAS limitations, genomic studies must integrate molecular surrogates for platelet-related phenotypes assayed in cell-based models derived from individuals of known genotypes and phenotypes. In our GWAS study of native platelet aggregation and aggregation in response to low dose aspirin (GeneSTAR, Genetic Study of Aspirin Responsiveness), 64 loci were associated with native platelet aggregation at genome wide significance (p<5x10"^) while 57 were associated with platelet responsiveness to aspirin, many replicated in both races. Although we are performing functional genomics studies to elucidate findings in known genes (PEAR1, RGL3, and MET), most signals were in intergenic regions (38%), or in introns (55%), with only 1.6% producing missense mutations in exons. Mechanistic interpretation is uncertain re which gene(s) are up- or down-regulated based on SNP modifications. In 3 phases, we will (1) create pluripotent stem cells (iPS) from peripheral blood mononuclear cells, and then differentiate these stem cells into megakaryocytes (2) efficiently produce iPS and megakaryocytes using a novel pooling method, and (3) produce iPS and megakaryocytes from 400 subjects in GeneSTAR (200 whites, 200 African Americans), selected based on specific hypotheses derived from GWAS signals in native and post aspirin platelet function; characterize genetic mRNA transcripts using a comprehensive Affymetrix exon array; measure protein expression for transcripts of interest using mass spectrometry; examine mRNA and protein expression patterns for each GWAS signal to determine the functional pathway(s) involved in native platelet phenotypes; and examine the functional genomics of variations in aspirin response using our prior genotyped and phenotyped population. This project at Johns Hopkins will be conducted by an interdisciplinary group of expert investigators. (Phase 1 and II, PI, L Cheng, Hematology Division, Dept of Medicine; Phase III PI, L Becker, GeneSTAR Research Program), RELEVANCE (See instructions): Precise information about the functional processes in megakaryocytes and platelets may lead to innovative and tailored approaches to risk assessment and novel therapeutic targets to prevent first and recurrent cardiovascular and related acute thrombotic events. Further, Phase I and II developmental research will contribute to new knowledge that would positively affect the transfusion of iPS-derived hematopoietic cells in patients with such cell deficiencies.

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Last updated: 2016-08-30T13:10:17.310-05:00

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