Dr. David Baltimore’s laboratory is involved in three major directions of research.
The first is study of the remarkable range of activity of the NF-kB transcription factor. It activates perhaps 1000 genes in response to a wide range of stimuli. It has different physiologic roles in different cells. How one factor can be so varied in its activity is the puzzle that interests us. Baltimore’s lab is studying this at the level of DNA-protein interactions as well as signal transduction pathways. They are studying its role in normal cells and in diseases like cancer and AIDS.
The second line of work involves using gene transfer methods to reprogram the immune system. Baltimore’s lab has shown that they can design a retrovirus vector able to express cDNA’s encoding both chains of the T-cell receptor (TCR) protein. When mouse hematopoietic stem cells are transduced with the vector and then inoculated into irradiated mice, many of the resulting T-cells express the TCR encoded by the vector. Baltimore’s lab has shown that when the TCR is able to recognize specific peptides from a tumor antigen, the animal can reject tumors carrying the antigen. They plan to extend these studies to human tumor antigens with the goal of developing a human therapy. They are also studying whether the same strategy will work for antibody gene expression by B-cells with a goal of devising a new therapy for AIDS.
The third goal of the laboratory is to understand the role of the Ryk protein as a co-receptor for Wnt proteins. Baltimore’s lab has shown that Wnt interacts with both Ryk and Frizzled surface receptor proteins in a tripartite complex. They are now investigating the pathways activated by Ryk and the role of Ryk in neuronal guidance.
Selected Cancer-Related Publications:
Boldin MP, Baltimore D. MicroRNAs, new effectors and regulators of NF-kB. Immunol Rev. 2012 Mar;246(1):205-20. doi: 10.1111/j.1600-065X.2011.01089.x.
Yang L, Boldin MP, Yu Y, Liu CS, Ea CK, Ramakrishnan P, Taganov KD, Zhao JL, Baltimore D. miR-146a controls the resolution of T cell responses in mice. J Exp Med. 2012 August 27; 209(9): 1655–1670. doi: 10.1084/jem.20112218
Yang L, Yu Y, Kalwani M, Tseng TW, Baltimore D. Homeostatic cytokines orchestrate the segregation of CD4 and CD8 memory T-cell reservoirs in mice. Blood. 2011 Sep 15;118(11):3039-50. doi: 10.1182/blood-2011-04-349746. Epub 2011 Jul 26.
O'Connell RM, Chaudhuri AA, Rao DS, Baltimore D. Inositol phosphatase SHIP1 is a primary target of miR-155. Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7113-8. doi: 10.1073/pnas.0902636106. Epub 2009 Apr 9.
Werner SL, Kearns JD, Zadorozhnaya V, Lynch C, O'Dea E, Boldin MP, Ma A, Baltimore D, Hoffmann A. Encoding NF-kappaB temporal control in response to TNF: distinct roles for the negative regulators IkappaBalpha and A20. Genes Dev. 2008 Aug 1;22(15):2093-101. doi: 10.1101/gad.1680708.