Virology, Immunology, Signal Transduction and Transcriptional Regulation
Our laboratory is involved in two major research thrusts. One is basic investigation of the development and functioning of the mammalian immune system. The other is Engineering Immunity: translational studies using viral vectors to carry new genes into immune cells to increase the range of pathogens effectively fought by the immune system and to make the immune system resist cancer growth more effectively.
Our basic studies have two directions: to understand the remarkable range of activity of the NF-kB transcription factor and to understand the normal and pathologic functions of microRNAS. NF-kB 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 has interested us for many years and that we have studied at many different levels.
MicroRNAs are small (~22 nucleotide) RNAs that regulate the amount of protein made by a particular messenger RNA and that therefore provide a level of fine control over gene expression. We have been interested in their role in hematopoietic cell development and function. We have recently concentrated on microRNAs that modulate myeloid cell development. Most interesting is miR-146a, which is a feedback regulator of NF-kB activation. A mouse knockout of the gene encoding miR-146a is normal at birth but slowly develops myeloid hyperproliferation and, ultimately, cancer. We have traced the earliest events to dysregulation of hematopoietic stem cells suggesting that a normal function of miR-146a is to be a guardian of hematopoietic stem cell health and longevity.
Our translational work centers on using gene transfer methods to reprogram the immune system. We first showed that we could design a retrovirus vector able to express cDNAs 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. When the TCR is able to recognize specific peptides from a tumor antigen, the animal can reject tumors carrying the antigen. We are extending these studies to TCRs that react with human tumor antigens with the goal of developing a human therapy. We have also developed therapies based on transfer of lentiviral vectors that encode small, interfering RNAs and vectors that carry antigen genes into dendritic cells. Because we found it difficult to make lentiviral vectors that would reprogram B cells to make specific antibodies, we switched to adeno-associated virus (AAV) vectors carrying genes that encode antibodies and have used them to reprogram muscle cells in mice to make anti-HIV and anti-influenza virus antibodies. Four programs that have emerged from these laboratory efforts are presently in clinical development, two in start-up companies and two in academic collaborations. We are also developing new programs that have clinical goals.