Shawn A. Mahmud

Degrees Received: B.A., Biology, St. Olaf College, Northfield, MN

Honors and Awards:   

American Society of Hematology Annual Meeting Travel Award, 2007
Microbiology, Immunology, and Cancer Biology Graduate Program Block Fellowship, 2007
Crohn’s and Colitis Foundation of America Student Research Fellowship Award, 2007
American Society of Hematology Annual Meeting Travel Award, 2006

Thesis Advisor:  Michael Farrar, Ph.D., MICaB Graduate Program

Thesis Research:       

CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) develop in the thymus and are indispensible for the prevention of systemic autoimmunity by restraining self-reactive T lymphocytes. The mechanism by which developing thymocytes are diverted to the Treg lineage remains unclear, but involves signaling originating from TCR/CD28 and the common gamma chain-dependent cytokine receptor, IL2Rbeta. Signaling through IL2Rbeta activates STAT5 to undergo nuclear translocation where it drives expression of foxp3, the master regulator of the Treg lineage. Transgenic mice expressing constitutively active STAT5 (STAT5b-CA) have a markedly larger Treg population, while STAT5-/- animals show a pronounced deficit. To elucidate the role of STAT5 in driving foxp3 expression, I will utilize BAC recombineering to generate Foxp3-BAC reporter mice with mutated STAT5 binding sites in the promoter and first intron of foxp3, which we predict will negatively regulate Treg development. I will also utilize chromatin immunoprecipitation (ChIP) and bisulfite sequencing techniques to clarify the role of STAT5 in recruiting chromatin-remodeling enzymes to the foxp3 locus which positively regulate its transcription. 

By augmenting our understanding of cytokine signaling in the transcriptional control of Treg development, these studies may ultimately contribute to the generation of novel therapeutics for treating autoimmunity or other chronic inflammatory disorders.

Publications:

Vang KB, Yang J, Mahmud SA, Burchill MA, Vegoe AL, Farrar MA.  IL-2, -7, and -15, but Not Thymic Stromal Lymphopoeitin, Redundantly Govern CD4+Foxp3+ Regulatory T Cell Development.  J Immunol 2008 181: 3285-3290.

Publications Prior to Entering MD/PhD Program:

Wang JG, Mahmud SA, Bitterman PB, Huo Y, Slungaard A. Histone deacetylase inhibitors suppress TF-kappaB-dependent agonist-driven tissue factor expression in endothelial cells and monocytes.  J Biol Chem. 2007;282:28408-28418.

Kowalska MA, Mahmud SA, Lambert MP, Poncz M, Slungaard A. Endogenous platelet factor 4 stimulates activated protein C generation in vivo and improves survival after thrombin or lipopolysaccharide challenge.  Blood. 2007;110:1903-1905.

Wang JG, Mahmud SA, Ngugen J, Slungaard A. Thiocyanate-Dependent Induction of Endothelial Cell Adhesion Molecule Expression by Phagocyte Peroxidases. A Novel HOSCN-Specific Oxidant Mechanism to Amplify Inflammation. J Immunol. 2006;177: 8714-8722.

 Wang JG*, Mahmud SA*, Thompson JA, Geng JG, Key NS, Slungaard A.  The principal eosinophil peroxidase product, HOSCN, is a uniquely potent phagocyte oxidant inducer of endothelial cell tissue factor activity: a potential mechanism for thrombosis in eosinophilic inflammatory states.  Blood 2006;107: 558-565.  (*Authors contributed equally to this manuscript)

Presentations and Posters Prior to Entering MD/PhD Program:

Mahmud SA, Wang JG, Wei P, Thomas MS, Belcher JD, Vercellotti GM, Slungaard A. The Thiol-specific Principal Oxidant Product of Phagocyte Peroxidases, HOSCN, Transcriptionally Induces Proinflammatory, Prothrombotic and Cytoprotective Gene Expression in Endothelium.  Gordon Research Conference: Thiol-based Redox Regulation and Signaling, 2008, Lucca, Italy. (Poster)

Mahmud SA, Wang JG, Wei P, Thomas MS, Belcher JD, Vercellotti GM, Slungaard A. The Major Phagocyte Peroxidase-derived Oxidant, HOSCN (Hypothiocyanous Acid), Induces Proinflammatory and Cytoprotective Gene Expression in Endothelium: A Mechanism for Microlocalized Regulation of Inflammation.  American Society of Hematology annual meeting 2007, Atlanta, GA. (Poster)

Mahmud SA, Wang JG, Slungaard A.  Thiocyanate-Dependent Inhibition of Spontaneous and Agonist-Induced Eosinophil Apoptosis by Eosinophil Peroxidase (EPO): A Potential Physiologic Role for Endogenously Generated HOSCN in Maintaining Eosinophil Viability.  American Society of Hematology annual meeting, 2006, Orlando, FL. (Poster)