We invite applications from talented and motivated postdoctoral candidates with relevant experience in mass spectrometry, analytical chemistry, imaging, instrumentation design, biochemistry, molecular biology, cell biology, computational biology, and related fields. Please send a statement describing your interests, a cv, and three letters of recommendation to firstname.lastname@example.org.
Candidates for graduate study should apply through the Chemical and Systems Biology (CSB) program. For application information and more details about the graduate program, please visit the CSB Departmental web site.
We invite motivated undergraduates with previous experience in genetics, biochemistry, molecular biology, cell biology, or computational biology. A minimum commitment of 12 hours per week, spanning two semesters and a summer, is expected.
Sample rotation projects:
- Uncovering the mechanism of how protein expression noise plays a critical role in regulating the fraction of cells in a homogenous population that undergo a cell fate decision for a given stimulus
The goal of this project is to understand the mechanistic origin of the cell-to-cell variability (noise) of protein expression that controls the number of cells that differentiate. We have previously shown that a bistable switch controls the conversion of preadipocytes to adipocytes and that stochastic variation in the expression of regulatory proteins is sufficient to explain how a submaximal stimulus triggers this switch in only a fraction of proliferating precursor cells rather than causes either all cells to differentiate or leaves all cells undifferentiated (Park et al, 2012). Intriguingly, our experiments and modeling showed that the expression levels of PPARγ, the master regulator of fat cell differentiation, are much less variable compared to the expression levels of other key regulators. This finding suggests the existence of active control mechanisms that selectively suppress the noise on PPARγ levels and thus provides us with an excellent system in which to uncover noise control mechanisms. These noise control mechanisms are likely critical for controlling the rate of many, if not most, cell fate decisions. Techniques include live-cell microscopy, expression of fluorescent proteins, siRNA, genome-editing with TALENS, and image analysis.
- Systems level analysis of the timing and feedback loops that drive the differentiation cell fate decision.
Our recent paper showed that we can use an activator of PPARgamma, rosiglitazone, to synchronize the adipocyte differentiation process (Park et al, 2012). We were able to show that the differentiation process is broken into clearly distinct time windows with one feedback loop engaging the next, which engages the next and so on. In this project, you would measure mRNA levels in each of these phases and determine the timing of all differentiation associated transciptional processes on a genomic scale using RNAseq. This will be a starting point to obtain a global understanding of the role of chromatin-remodelers, transcription factors, signaling proteins and others that regulate each phase of the differentiation process – the identified regulators may ultimately serve as novel targets for therapeutic intervention. The dataset you will be obtaining in the rotation would also be a foundation for exciting future projects. You would learn in this rotation next-generation, high-throughput sequence technology.
- Expanding our quantitative mass spectrometry approach to investigate the assembly of critical chromatin remodeling processes.
One of the interesting outstanding questions about irreversible cell fate decisions is the connection between cell signaling, transcriptional feedback loops and the parallel occurring reorganization of chromatin. We are currently expanding the list of regulatory proteins that changes we can quantify as a function of time to include a comprehensive list of critical chromatin remodeling proteins. You would learn in this rotation project quantitative mass spectrometry based on a triple Quad and using isotope labeled peptides for absolute quantification of changes in critical protein levels and posttranslational modifications. These studies will also be an exciting starting point addressing the timely question of how the chromatin, transcriptional and signaling regulatory circuit interconnects. This project would provide a critical foundation for an exciting potential thesis project.
- How do hormonal oscillations that happen with frequencies of minutes to days link to fat cell production? Mammals show oscillations in hormone secretion – we do not know if and how this affects cell fate decisions. Our lab has now in place an ideal system to test if and how such oscillations control differentiation using adipocytes as a model system and by focusing on insulin and glucocorticoids oscillations. Previous in vitro studies always used constant stimuli to induce differentiation but several arguments point to a key role of oscillations. The single-cell imaging approaches we recently developed allow us now to test the hypothesis that the body has setup a system where certain pulse patterns selectively regulate the all-or-none decision to switch from proliferating preadipocyte into non-dividing, lipid-accumulting adipocyte (we think that this control would be lost fo constant stimuli). We believe that this may explain why aging, Cushing’s disease, overeating, and other conditions where the secretion of hormones loses its pulsatile manner are so strongly correlated with obesity. In this project you may discover a new regulatory principle (this could be the key part of a first author paper for you), and you would learn automated single cell imaging and analysis.
- Chemical screening for novel regulators of adipogenesis
We have recently purchased the NIH clinical collection small molecule library (http://www.nihclinicalcollection.com/chemical ). In this project you could be screening this library of about 1000 compounds and discover regulators that control fat mass. These already clinically approved drugs include therapies that target for example foot fungal disease, anti-depressives, and blood-clotting agents and several of them may have undiscovered second application in the treatment of obesity. By doing this, you will learn high-throughput, cell-based screening approaches as well as automated single cell imaging and analysis and this project could then be continued as part of the SPARK program.