The study of hematopoietic system at the molecular has yielded many new insights and therapies, from use of erythropoietin to manipulation of acute promyelocytic leukemia with all-trans retinoic acid. The powerful steroid hormone receptor superfamily has many active members in the hematopoietic system, but many have only just been discovered, and the potential for new therapies through manipulation the receptor ligands is only just beginning to be explored. The author of this proposal is a young board-certified academically oriented pathologist, now a hematopathology fellow at the University of Chicago. She as long term interests in the molecular at UCLA and the University of Chicago, on nuclear receptors present in the bone marrow compartment, whit a focus on a new human member of the superfamily, the peroxisome proliferator activated receptor gamma (hPPAR g). The author now proposes to look in depth at this nuclear receptor, which regulates transcription when activated by binding its ligand, putatively an arachidonic acid metabolite. HPPAR g is likely to affect prostaglandin and leukotriene catabolism through regulation of the key enzyme of the w hydroxylation pathway. The hPPAR g has two different transcripts expressed in hematopoietic cells, the circumstances of which appear complex. The author proposes to: 1) analyze and compare the sequences of the two transcripts, 2) determine whether both are translated into protein, and 3) examine whether they both activate transcription in response to ligand, and if so, 4) determine whether they can heterodimerize, both with each other, and with other likely partners of the nuclear receptor superfamily also present in the bone marrow compartment (retinoic acid receptor, retinoid orphan receptor, and retinoid X receptor). To further analyze the affect of the hPPAR g protein(s) on transcriptional activation, 5) chimeric receptors will be constructed, interchanging nuclear receptor functional domains to determine the contribution of the different hPPAR g regions on heterodimerization and transcriptional activation. Finally, the author propose to search for the natural ligand of hPPAR g by (6) testing a variety of arachidonic acid metabolites present in monocytes and neutrophils for their ability to activate hPPAR mediated transcription in a reporter system.
| Rosenfield, R L; Deplewski, D; Greene, M E (2000) Peroxisome proliferator-activated receptors and skin development. Horm Res 54:269-74 |
| Greene, M E; Pitts, J; McCarville, M A et al. (2000) PPARgamma: observations in the hematopoietic system. Prostaglandins Other Lipid Mediat 62:45-73 |
