Molecular Biology and Genetics
My laboratory uses molecular biology approaches in an effort to better understand retinal function and pathology, and attempts to use this increased understanding to develop new approaches for the diagnosis and treatment of retinal disease (age-related macular degeneration, retinitis pigmentosa, and glaucoma). We are particularly interested in defining the mechanisms regulating photoreceptor and ganglion cell gene expression, determining how gene expression changes in disease, and identifying and characterizing novel retinal genes that are important for retinal function and disease.
Molecular genetics is built on the assumption that DNA sequence alone is sufficient to direct a cell's creation, operation, and fate. While this assumption must be modified to accommodate epigenetic phenomena, it is at least clear that the information contained solely in the sequence of the genome is massive and complex. We use sequence alignment algorithms, phylogenetics, and sequence modeling to form hypotheses about historic and current roles of DNA features.
Cell membranes are sites of interface between the cell and the outside world, and constitute major sites of signaling. Membranes also form the front lines where deadly pathogens first contact human cells and initiate infection. Our main focus is a family of membrane-immersed enzymes, termed rhomboid proteases, that cut protein segments within the membrane. This cleavage liberates proteins from the membrane, either to activate signals rapidly, or to inactivate selected targets.
The binding and presentation of peptide fragments to T lymphocytes by histocompatibility molecules is a central event in regulating the immune response to self and non-self antigens. My group has focused on the study of a novel family of conserved class I histocompatibility proteins termed class Ib molecules. We have found that one member of this family, the Qa-1 molecule encoded by the class Ib gene T23, binds peptides derived from bacterial and mammalian stress (heat-shock) proteins.
Our lab studies the earliest stages of embryogenesis to understand how single-celled eggs develop into complex multicellular embryos. We focus on the choice between soma and germline, one of the first developmental decisions faced by embryos. Our goal is to identify and characterize the molecular mechanisms that activate embryonic development, polarize embryos, and distinguish between somatic and germline cells.
For the 34 million people infected with HIV-1, the best current hope for avoiding the fatal consequences of the infection lies in treatment with antiretroviral therapy (ART), which consists of combinations of three drugs that inhibit specific steps in the virus life cycle. The benefits of ART in reducing the morbidity and mortality are clear, but ART is not curative. In 1995, our laboratory provided the first demonstration that latently infected CD4+ T cells were present in patients with HIV-1 infection. We later found that latently infected cells persist indefinitely even
A fundamental property of living cells is their extraordinary ability to sense and respond to a changing environment. In higher eukaryotes, malfunctioning of signaling networks has many devastating consequences such as cancer, diabetes or autoimmunity. Such consequences arise from the inability of cells to properly evaluate information and cooperate. Our main focus is to understand how individual cells use signaling networks to integrate information, and eventually coordinate collective cell behaviors.
The mammalian olfactory system provides an excellent model to study two of the important questions in molecular neurobiology. The continual replacement of olfactory receptor neurons mimics many aspects of neuronal differentiation and development in the brain. The olfactory system, therefore, provides a unique opportunity to observe processes in adults that, in other neuronal systems, only occur in the embryo. Additionally, the mammalian olfactory system has the remarkable ability to detect a wide variety of odorant molecules with high sensitivity and specificity.
Biology: Frizzled receptors in development and disease Our laboratory has focused for the past two decades on a large family of cell-surface receptors called Frizzled. This name refers to the appearance of fruit flies in which the receptor gene is mutated: the hairs and bristles on the body surface of Frizzled mutant flies are oriented inappropriately. In mammals, including humans, there are ten closely related Frizzled genes. In the mid-1990s, we showed, in collaboration with the laboratory of Roel Nusse at Stanford, that the principal ligands for Frizzleds are the Wnt proteins.
Molecular mechanisms underlying accurate chromosome segregation