German A. Enciso, Ph.D. - US grants

We propose a program to enhance the training and career development of scientists who seek to undertake interdisciplinary biological and biomedical research that draws upon ideas and tools from mathematics, physics, engineering and computer science, as embodied by the young field of Systems Biology. The program is centered upon a three-week intensive course at UC Irvine, followed by one to two years of follow-up mentoring and career development activity. The course is intended for graduate students, postdocs and more advanced scientists, both those with backgrounds in experimental biology?who typically need additional preparation in mathematics and computation?and those with backgrounds in mathematics, physics, engineering or computer science?who usually need additional preparation in the foundations of biology. We aim to train around 20 individuals each year. The proposed program begins with a one-week preparatory workshop, followed by a two-week core course in which lectures and laboratory modules will expose participants to cutting-edge interdisciplinary methodologies and research topics. The program will also feature extensive mentoring and career-skill building activities, including panel discussions, presentations, mentored team projects, and individually-guided development of research or fellowship proposals. These activities will involve 27 UCI faculty with research and teaching expertise in mathematics, physics, computer science, engineering and the biological sciences. Outreach activities include dissemination of information through online resources and a systems biology regional conference, as well as participation in workshops at interdisciplinary and minority conferences. The specific goals of the course include (i) conveying an understanding of Systems Biology and its interdisciplinary nature; (ii) filling gaps in technical expertise and vocabulary, and developing a deep understanding of mathematical models; (iii) acquainting participants with the challenges of collaboration and communication in interdisciplinary research, (iv) fostering community building, and (v) enhancing career development. Lecture materials (video-recorded), training datasets, and software tools will be made freely available through on-line distribution to maximize outreach. Course administration and logistics will be handled by the UC Irvine Center for Complex Biological Systems (CCBS), an NIH-designated National Center for Systems Biology.

Project Summary/Abstract Chlamydia genital infections are the most commonly reported infection in the U.S. All Chlamydia species cause an unusual intracellular infection in which there is conversion between a dividing form of the bacterium (reticulate body or RB) and the infectious form (elementary body or EB). RB-to-EB conversion is critical for producing infectious progeny that can spread the infection to a new host cell, but the mechanisms that regulate it are unknown. There has been a longstanding assumption in the Chlamydia field that conversion is regulated by an extrinsic factor. However, we have obtained data to support a new regulatory mechanism in which RB size is used as an intrinsic factor to control conversion. Based on temporal measurements of chlamydial size and number obtained with three-dimensional electron microscopy (3D EM), we hypothesize that RBs undergo size reduction through successive rounds of replication and can only convert into an EB below a size threshold. In Aim 1, we will test this size control mechanism by determining whether RB size is altered when the timing of RB-to-EB conversion onset is changed. In Aim 2, we will investigate if the size of the first RB plays a role in starting the timer of RB size reduction that eventually culminates in RB-to-EB conversion. In Aim 3, we will study how RB size could be used to regulate conversion. We propose a titration mechanism in which EUO, a repressor of late chlamydial genes, is titrated away in smaller RBs to promote conversion. In Aim 4, we will study alternative mechanisms that utilize extrinsic signals to control conversion. Using mathematical modeling and 3D EM analysis, we will test a contact-dependent mechanism, which is based on contact of the RB with the inclusion membrane as the external signal, and a chlamydial communication mechanism in which the external signal is produced by other chlamydiae. These studies will provide important information about the mechanism of RB-to-EB conversion that can be applied in new therapeutic strategies to block the developmental cycle and the production of infectious progeny.