Schrader, John
Associate Member, Dept of Pathology and Laboratory Medicine
Research Interests
Our research has two major themes:- understanding how the production and function of lymphohemopoietic cells is regulated and how antibodies are generated and can be exploited as research tools or therapeutics. It is relevant to inflammatory diseases like rheumatoid arthritis and asthma, infectious diseases, as well as to breast cancer and leukemia.
Our work on the regulation of hemopoietic cells has focused on M-Ras, a new member of the Ras family of molecular switches we identified through bioinformatic approaches , as well as on its binding partners we have identified using yeast-two hybrid screens or affinity-directed mass spectrometry. These include an activator of M-Ras called smgGDS and a novel effector protein, the Ras Pathway Modulator (RPM). Structural similarities between M-Ras and the "classical " p21 Ras proteins, mean that some functions of M-Ras may have been misattributed to classical p21 Ras. M-Ras shares many, although not all, of the effectors and positive- and negative-regulators of p21 Ras. We have shown that M-Ras however is preferentially activated over H-Ras by growth factors like epidermal growth factor and hemopoietic growth factors. However, unlike p21 Ras, M-Ras is not activated at all by ligation of the antigen receptors on T or B lymphocytes. We are interested in the activation of ras pathways downstream of the Toll-Like-Receptors that sense productus of micro-organisms. We are currently analyzing mice with null mutations of M-Ras.
We serendipitously discovered a novel protein that was strongly upregulated when resting T or B lymphocytes were activated. We used mass spectrometry to identify it as a protein with two novel domains that we called Caprin-1. Caprin-1 has a homologue, Caprin-2, and both are highly conserved in vertebrate evolution. Caprin-1 is also expressed in all dividing cells as well as in the brain. We have shown using gene targeting that Caprin-1 is essential for cell growth and are currently using proteomic approaches to uncover its biochemical function.
Using our SLAM technique, we generated a series of human monoclonal antibodies against a virus human cytomegalovirus (HCMV) that is present in most humans and, if not controlled by a healthy immune system, causes serious diseases. These monoclonal antibodies targeted a critical site on HCMV and neutralized its ability to infect cells. Surprisingly antibodies generated from different individuals were all derived from genes that had been generated by the recombination of the same three VH, JH, and Vk germline elements. Given that these particular germline elements are present in all humans, we hypothesized that they had been selected for during human evolution to enable humans to generate germline-based, unmutated antibodies that would bind HCMV and predictably generate high-affinity neutralizing antibodies through subsequent somatic mutation. To test this idea, we recreated the hypothetical germline-based encoded antibodies, and confirmed that they indeed bound the HCMV epitope. We are studying in detail the three-dimensional structure of these germline-based antibodies and comparing them with those of the somatically mutated high-affinity progeny. The germline-based response to HCMV may be a paradigm for those against critical molecular entities on other pathogens.