School of Medicine
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Assistant Professor of Chemical and Systems Biology
Current Research and Scholarly InterestsResearch in my laboratory is aimed at understanding how eukaryotes replicate their DNA despite numerous challenges (collectively known as replication stress), and more generally – how eukaryotic cells safeguard genome integrity. Specifically, we are investigating: (i) mechanisms that regulate the activity of the replicative helicase during replication stress, (ii) mechanisms that control the inheritance of epigenetic information during replication, and (iii) mechanisms of ubiquitin-mediated regulation of genome maintenance. We utilize single-molecule microscopy to directly image fluorescently-labeled replication factors and track them in real time in Xenopus egg extracts. I developed this system as a postdoctoral fellow, and used it to monitor how the eukaryotic replicative helicase copes with DNA damage. We plan to further extend the capabilities of this platform to directly visualize other essential replication factors, nucleosomes, and regulatory post-translational modifications like ubiquitin chains. By elucidating molecular mechanisms responsible for maintaining genome stability, we aim to better understand the link between genome instability and cancer, and how these mechanisms can be harnessed to improve disease treatment.
Professor of Chemical and Systems Biology and, by courtesy, of Biochemistry
Current Research and Scholarly InterestsGenomic instability contributes to many diseases, but it also underlies many natural processes. The Cimprich lab is focused on understanding how mammalian cells maintain genomic stability in the context of DNA replication stress and DNA damage. We are interested in the molecular mechanisms underlying the cellular response to replication stress and DNA damage as well as the links between DNA damage and replication stress to human disease.
Professor of Bioengineering and, by courtesy, of Chemical and Systems Biology
Current Research and Scholarly InterestsOur focus is on building computational models of complex biological processes, and using them to guide an experimental program. Such an approach leads to a relatively rapid identification and validation of previously unknown components and interactions. Biological systems of interest include metabolic, regulatory and signaling networks as well as cell-cell interactions. Current research involves the dynamic behavior of NF-kappaB, an important family of transcription factors.
Postdoctoral Research Fellow, Chemical and Systems Biology
Current Research and Scholarly InterestsInvestigating the role of R-loops in genome instability and cancer.
Justin Du Bois
Henry Dreyfus Professor in Chemistry and Professor, by courtesy, of Chemical and Systems Biology
BioResearch and Scholarship
Research in the Du Bois laboratory spans reaction methods development, natural product synthesis, and chemical biology, and draws on expertise in molecular design, molecular recognition, and physical organic chemistry. An outstanding goal of our program has been to develop C–H bond functionalization processes as general methods for organic chemistry, and to demonstrate how such tools can impact the logic of chemical synthesis. A second area of interest focuses on the role of ion channels in electrical conduction and the specific involvement of channel subtypes in the sensation of pain. This work is enabled in part through the advent of small molecule modulators of channel function.
The Du Bois group has described new tactics for the selective conversion of saturated C–H to C–N and C–O bonds. These methods have general utility in synthesis, making possible the single-step incorporation of nitrogen and oxygen functional groups and thus simplifying the process of assembling complex molecules. To date, lab members have employed these versatile oxidation technologies to prepare natural products that include manzacidin A and C, agelastatin, tetrodotoxin, and saxitoxin. Detailed mechanistic studies of metal-catalyzed C–H functionalization reactions are performed in parallel with process development and chemical synthesis. These efforts ultimately give way to advances in catalyst design. A long-standing goal of this program is to identify robust catalyst systems that afford absolute control of reaction selectivity.
In a second program area, the Du Bois group is exploring voltage-gated ion channel structure and function using the tools of chemistry in combination with those of molecular biology, electrophysiology, microscopy and mass spectrometry. Much of this work has focused on studies of eukaryotic Na and Cl ion channels. The Du Bois lab is interested in understanding the biochemical mechanisms that underlie channel subtype regulation and how such processes may be altered following nerve injury. Small molecule toxins serve as lead compounds for the design of isoform-selective channel modulators, affinity reagents, and fluorescence imaging probes. Access to toxins and modified forms thereof (including saxitoxin, gonyautoxin, batrachotoxin, and veratridine) through de novo synthesis drives studies to elucidate toxin-receptor interactions and to develop new pharmacologic tools to study ion channel function in primary cells and murine pain models.