Algebraic K-theory by Daniel R. Grayson

By Daniel R. Grayson

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This is an essential step for identifying molecules that are necessary for cardiac pain but not for other sensations. Our initial work fmds that cardiac afferents have a unique molecular fmgerprint: they express an extremely Sensitive acid-sensing ion channel at grossly high levels. The result underscores the importance of protons created during ischemia as a mediator of cardiac pain. Our specific aims will: 1) definitively identify the particular clone of acid-sensing ion channel used by cardiac afferents; 2) fmd whether other putative mediators of cardiac pain act by modulating this channel; 3) explore why there is different expression of channels in the two different populations of cardiac afferents.

This application has three specific aims. In the first aim, we will characterize intracellular pathways that are required for activating beta-globin gene expression. The second aim will focus on the molecular mechanisms by which intracellular pathways for beta-globin gene expression silence the gamma-globin gene, In the third aim, we will examine whether expression of the gamma-globin gene is induced in primary erythroblasts of the beta-globin disorders and adult mice which have low activities of intracellular pathways for beta-globin gene expression.

We will examine these polyamides in primary human bone marrow and umbilical cord erythroid cells for their effectiveness in inhibiting betaglobin expression in vivo. In addition, we will design new polyamides with the goal to activate gamma globin gene expression directlv. Studies in Specific Aim II will test a novel viral vector for its capacity to express a transgene in a fashion that is resistant to gene silencing. One major limitation of viral vectors is that they are often subject to gene silencing, especially in hematopoietic (HS) and embryonic stem (ES) cells and their differentiated progeny.

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