Research

Philip Andrews
Faculty Profile

Project Title: Mapping protein complexes: structures, interaction dynamics, and drug target sites
Project Description:  
One major project in our lab focuses on development of new classes of chemical crosslinkers with greatly improved characteristics for mapping protein complexes and characterizing unknown protein structures.   These tools have been applied to several large protein complexes (including Hsp70 complexes, GRASP55, and MLL1) and are being extended to whole mitochondrial and Golgi membrane protein complexes.  The long-term goal of this new research project is to determine the dynamics of protein interactions in vivo to better understand cell processes and to identify druggable interaction sites.

More broadly, our research focuses on systems analysis and protein structures through mapping protein interactions and how they are modulated by post-translational modifications.  A continuing effort of our laboratory has been development and application of computational methods in proteomics and the application of new chemistries and techniques in structural mass spectrometry.  Recent work in the Andrews’ laboratory has focused on the molecular architectures of organelles (and how they change with physiology), methods for quantitative proteomics (including phosphoproteome and histone post-translational modifications), approaches to improving interaction maps, computational methods for analysis of proteomics data, and mapping solution-phase changes in protein structure.  Our lab collaborates with a number of other groups to elucidate cell control pathways.

Charles L. Brooks III
Faculty Profile
Lab Website

Project Title:  In Silico Drug Discovery and Development
Project Description:
Our laboratory is focused on the application of statistical mechanics, quantum chemistry and computational methods to chemically and physically oriented problems in biology. Key questions of current interest involve free energy-based methods for inhibitor screening and optimization, including lambda-dynamics and multi-site lambda dynamics – novel statistical mechanical methods to enable the high throughput in silico screening of large databases of small molecule inhibitors, and ligand docking and discovery methods.

Students joining the project would work with a team of graduate students and postdocs to assist in large-scale screening benchmark studies that are currently underway in the laboratory. These studies involve the application of computing infrastructure, hardware with significant GPU acceleration and novel free energy software that is part of the CHARMM biomolecular simulation package, to explore ligand – protein receptor binding free energies. Additional projects could involve work with a team of graduate students on docking benchmarks using developing methods for protein – ligand docking to test and evaluate evolving methodologies in the group. Some comfort with using computers is suggested, but not required, as students will learn how to work in our environment from other team members through structured mentoring.

Timothy Cernak
Faculty Profile
Lab Website

Project Title: Chemical synthesis at the interface of data science
Project Description: 
Chemical synthesis is a primary tool in the invention of medicines and biochemical probes. A large amount of data must be collected and interpreted in the chemical synthesis step and in the product characterization step. Our lab uses data science and high-throughput chemical experimentation techniques to navigate this near-infinite reaction space and chemical space in the hunt for new drugs. We look for unanticipated patterns and trends in reaction data, and use our findings to develop new reactions of importance to medicinal chemists. The Cernak Lab is outfitted with robotics and other tools for organic synthesis, high-throughput experimentation, high-throughput analysis and data analysis. Students typically learn cutting-edge techniques in these areas and should expect to run both wet chemistry experiments and computational informatics studies. Talented undergraduates hone their skills in modern chemical synthesis, high-throughput experimentation, automation and data science. REU students typically work towards the invention of a new chemical reaction that would be impactful in drug discovery.

Mara Duncan
Faculty Profile
Lab Website

Project Title: Understanding the proteins important for Membrane traffic
Project Description:
Membrane traffic is essential for the normal functioning of our bodies, because maintains the proper functioning of many membrane bounded organelles, including the plasma membrane, Golgi, ER, and lysosome. Importantly, it is the mechanism by which cells can control the content of their plasma membrane, which is important for many processes including cell communication, adhesion, and migration. The Duncan lab studies the proteins that are important for membrane traffic using a combination of genetic, biochemical, and cell biological approaches. One currently available REU project looks at components of a conserved complex that is required for membrane traffic. This project will include structure-function analyses in vivo and in vitro to map functionally important regions of the protein and physical interactions between the complex subunits. A second project looks at a novel protein inhibitor of type V myosins. Students will be involved in testing specific protein-protein interactions using recombinant proteins. Techniques learned will include yeast and bacterial culturing techniques, molecular genetics including generating mutant alleles and fluorescently tagged proteins, recombinant protein purification, and fluorescence microscopy.

Roland Kersten
Faculty Profile
Lab Website

Project Title:  Discovery and engineering of plant natural products from the University of Michigan Botanical Garden
Project Description:
Plants are a traditional source for medicines. Ancient civilizations developed pharmaceutical systems based on their surrounding floras and these herbal medicines are still widely used in most parts of the world. The medicinal properties of plants are often caused by small molecules called natural products. It is estimated that every plant has the capacity to produce thousands of natural products, most of which are chemically and pharmaceutically uncharacterized. My lab is interested in uncovering new natural products from the plant kingdom with potential applications to cure human diseases in a chemically systematic way. This project aims to characterize new plant peptide natural products from diverse plants of the University of Michigan Botanical Garden. Peptides are small proteins, which have beneficial properties for drug development such as target binding specificity and easy structural diversification by genetic engineering of peptide biosynthetic genes. The project involves collection of diverse plant samples from the Matthaei Botanical Garden, chemical extraction of peptides from collected plant samples, chemical analysis of extracts by mass spectrometry and data analysis for peptidic signatures in the collected mass spectrometry data. For newly identified peptides, biosynthetic genes will be characterized from source plants and heterologously expressed in tobacco to enable a sustainable source-plant-independent production of the peptides and a genetic platform for future peptide diversification. REU students will learn plant genomics, mass spectrometry and plant synthetic biology approaches. The results will broaden our knowledge of peptide chemistry in the plant world and guide future natural product discovery.

Anna Mapp
Faculty Profile
Lab Website

Project Title: Towards a Molecular-Level Picture of Gene Transcription
Project Description:
Altered transcriptional patterns are associated with all human diseases, either as a cause or as an effect. For this reason, molecules that interfere with or promote protein-protein interactions within the transcriptional machinery are attractive targets for therapeutic development and as mechanistic probes. Only a handful of such molecules have been reported, however, due in large part to the still-limited understanding of the mechanism of transcriptional regulation. The Mapp lab uses a combination of synthetic, biochemical, and cell biology approaches to develop a molecular-level picture of key protein-protein interactions in transcription initiation and use that information to design small molecules that mimic essential features of transcription factor structure and function. Current REU projects include using in vivo cross-linking to discover key protein-protein interactions that lead to a gene being turned on and using NMR spectroscopy to study the conformational changes in transcriptional proteins induced by small molecule transcriptional activators. An REU student will learn a variety of techniques from organic synthesis to protein expression to protein NMR.

James Moon
Faculty Profile
Lab Website

Project Title:  ImmuoEngineering
Project Description:
The Moon Laboratory at the University of Michigan is developing new immunotherapies and vaccines at the interface of immunology and engineering. We design new drug delivery systems for improving immune functions in the context of cancer, infectious pathogens, and autoimmunity. Students will use a variety of methods including nanomaterials, polymer and scaffold synthesis, organic chemistry, analytical chemistry, biochemistry, advanced microscopy, and whole animal in vivo imaging for the design and development of new immunomodulatory drugs.

Zaneta Nikolovska-Coleska
Faculty Profile
Lab Website

Project Title: Towards Developing Molecularly Targeted Small Molecule Inhibitors
Project Description:
The research focus of Nikolovska-Coleska’s group is discovery, design and development of small-molecules as new molecularly targeted therapies for cancer. Molecularly targeted therapy is a treatment that aims to interfere with the function of the biological pathway within the cancer cell that is critical to its growth or survival. By targeting a unique characteristic of the tumor, cancer cells will be specifically killed, providing effective cancer treatment with significantly fewer side effects. We use different strategies to identify new hits and lead compounds, such as high throughput screening, virtual screening and structure-based design. One of the current lab focuses is targeting protein-protein interactions involved in programmed cell death and we are working on developing small molecule inhibitors of myeloid cell leukemia-1 (Mcl-1), a potent anti-apoptotic molecule, member of the Bcl-2 family of proteins. Mcl-1 has been found to be overexpressed in both solid and non-solid tumor cell lines and human cancer tissues. Consistent with its anti-apoptotic function, overexpression of Mcl-1 has been associated with tumor initiation, progression and resistance to current anticancer therapies. Our lab has identified several lead compounds and currently we are optimizing these compounds through a structure-based drug discovery approach supported by experimental structural biology, molecular modeling, chemical synthesis, and biochemical and biological in vitro and in vivo evaluation. The second focus of our research is in epigenetics modifications which play an important role in human cancer. Particularly we are interested in protein-protein interactions that underline the histone modifications, specifically histone methylation and elucidating the biological role of histone lysine methyltransferases (HKMases). For this purpose we have biochemically characterized the protein-protein interactions between Dot1L, a K79 specific histone lysine methyltransferases and MLL-fusion proteins using surface plasmon resonance (SPR). Mutagenesis and structural characterization of these protein-protein interactions are underway. By applying a chemical screening approach we have identified molecules that inhibit enzymatic activity of Dot1L. Using these chemical probes as pharmacological tools, we are performing different cell-based functional assays in order to further elucidate and understand the function of Dot1L and its importance in leukemia. The REU student could be involved in either of these two projects based on his/her interest. The REU student will be exposed to and learn a variety of techniques from organic synthesis, complementary biochemical (fluorescence polarization based binding assay, tritium scintillation proximity enzymatic assay) and biophysical assays (SPR and NMR), functional and cell based assays using different human cancer cell lines for validation and characterization of new small molecule inhibitors.

Patrick O’Brien
Faculty Profile
Lab Website

Project Title: Molecular Mechanisms of DNA Repair
Project Description:  
Our genomes are under constant attack from endogenous and exogenous sources of chemical damage. Fortunately, many pathways exist to survey genomic DNA, remove chemical lesions, and restore the original sequence. Failures in DNA repair can cause a wide variety of diseases, including cancer and neurodegeneration. Therefore, a molecular understanding of DNA repair pathways is critical for understanding disease risk and recent progress is leading to novel strategies to treating diseases such as cancer. REU students have the opportunity to learn biochemical and biophysical approaches to studying enzyme mechanisms and specificity in protein-protein and protein-DNA interactions. Specific projects are designed based on the interests of the student and on the feasibility in relationship to current research in the lab. Past student projects have developed new biochemical assays, characterized new small molecule inhibitors, and determined catalytic specificity and chemical mechanism.

Stephen Ragsdale
Faculty Profile
Lab Website

Project Title: Role of Metal-Containing Cofactors in Biochemistry
Project Description: 
The efforts of the Ragsdale laboratory focus on studying the roles of metallocofactors in the structure and function of proteins. In several projects, we are studying the catalytic role of metal-containing cofactors (vitamin B12, heme, a nickel-tetrapyrrole, iron-sulfur clusters). The processes that we study involve key microbial reactions in the global carbon cycle (carbon dioxide fixation, methane synthesis, carbon monoxide metabolism). We also are determining the mechanism of mercury methylation. In another project we are determining how heme is used to regulate metabolism and the circadian rhythm in mammals. REU students have the opportunity for training in a wide array of biological and biochemical skills involving the culture of diverse microbes or human cells; performing protein purification; measuring enzyme activity and spectroscopic analyses; making and characterizing site-directed variants of proteins.

Kaushik Ragunathan
Faculty Profile
Lab Website

Project Title:  Reverse engineering epigenetic memory in eukaryotic cells
Project Description:

Our bodies consist of billions of genetically identical cells that have the capacity to exhibit distinct phenotypic states. These processes, known as epigenetics, are fundamental to multicellular development where cells maintain unique identities that last throughout our lifetimes. This capacity of cells to alter gene expression patterns without any changes to their genomes also enables adaptation, rapid evolution, and heterogenous cellular responses. We do not understand the molecular properties of the underlying code that creates such extensive diversity. My lab is interested in understanding the molecular properties of the epigenetic code and reverse engineering this process using genetics and biochemistry. 

Specific projects include:

• Saturation mutagenesis of HP1 proteins to identify key protein-protein interaction residues involved in epigenetic inheritance
• Use in vitro evolution approaches to design new tools to track epigenetic modifications. Students interested in this type of work will be exposed to highly interdisciplinary, inclusive and collegial atmosphere consisting of students from chemistry, biology, bioinformatics, biochemistry and genetics.  Through this, students will be exposed to a wide range of valuable laboratory techniques. We strive to create an inclusive atmosphere that encourages self-learning and independent thinking.

Gus R. Rosania
Faculty Profile
Lab Website

Project Title: Microscopic image-based analysis of small molecule subcellular transport
Project Description: 
My laboratory studies the transport of small bioactive molecules within single living cells using a multidisciplinary approach spanning high throughput microscopic imaging, machine vision, biochemical analysis, chemical genomics, mathematical modeling, and cheminformatics. The goal is to elucidate the relationship between the chemical structure of small molecules and their intracellular distribution, while developing methods for optimizing intracellular transport properties of small molecules by introducing chemical modifications into said molecules, to impart favorable subcellular distribution properties. These studies are essential to our understanding of how cells interact with toxins present in the environment, as well as how cells transport nutrients and rid themselves of metabolic waste products. Specific research projects center on studying cellular transport properties of small molecules, and developing methods to quantitatively assess the mass or concentration of small molecules in different subcellular compartments at different times after cells are exposed to chemical agents, as well as visualizing microscopic imaging data. Small molecule transport can be easily and safely monitored semiquantitatively using microscopy. Undergraduate students participating in the REU program will be paired with graduate students in the lab, with whom they will learn the basics of microscopic image acquisition, analysis and display techniques that are used to elucidate the subcellular accumulation of fluorescent drug-like molecules. They will also study the mechanisms by which small molecule drugs can precipitate inside cells, and will study the interaction between drug crystals and biomolecules in the context of drug discovery and development.

Les Satin
Faculty Profile
Lab Website

Project Title: Role of Metabolism in Insulin Secretion Oscillations
Project Description:
The Satin lab is interested in understanding the cellular and molecular basis of insulin secretion from pancreatic beta cells in both healthy and diabetic animals, and islets from humans.  Our unique focus are interactions between ion channels of the beta cell plasma membrane and fuel metabolism of the beta cell.  Our work on interactions of metabolism and ion channels includes the development of novel genetically encoded metabolic sensors for glucose metabolites, intracellular ion measurements, metabolomic analysis, and studies of genetically modified mice, as well as human islets. We have new work underway that seeks to understand how the function of beta cells in response to insulin resistance may in turn alter the mass of beta cells capable of secreting insulin.  

We are also interested in understanding how abnormalities in endoplasmic reticulum calcium levels contribute to ER stress, and the impact of ER Ca changes on various protein folding diseases, of which diabetes is one example.  We are also studying gap junctions and their role in beta cell to beta cell communication within the islet.  Our overall goal is to improve our understanding of the cellular mechanisms controlling oscillatory insulin secretion, and to improve the treatment of diabetes through the development of new drugs targeting the stimulus-secretion coupling pathway.

Anna Schwendeman
Faculty Profile

Project Title: Optimization of HDL Nanomedicines for Treatment of Heart Disease
Project Description: 
High density lipoprotein (HDL or "good" cholesterol) works by removing excess cholesterol from macrophages in plaques and transporting it to the liver for elimination. Artificial HDLs nanomedicines, hyperbolically called “Drano® for the arteries”, are being tested in clinical trials. The HDL is a natural nanoparticle (10 nm in diameter) composed of apolipoprotein A-I and phospholipids. The objective of this research project is to understand how the size and lipid composition of HDL affects its cholesterol binding properties and, therefore, its potency in cell culture and in animals. Undergraduates will examine protein-phospholipid binding efficiency by titration micro-calorimetry and prepare a variety of HDL nanoparticles. HDLs will be analyzed by chromatography, particle sizing methods, gel electrophoresis and microscopy. The affinity of HDL nanoparticles for cholesterol will be determined by micro-calorimetry and fluorescent spectroscopy, and tested in cell culture. Undergraduates will learn a variety of useful research methodologies and participate in designing novel efficacious and safe HDL nanomedicines for treatment of patients with heart disease.

David H. Sherman
Faculty Profile
Lab Website

Project Title: Marine Microbial Discovery and Analysis
Project Description: 
The efforts of the Sherman laboratory to isolate novel marine bacteria involve field collection of sediments, sponges, and other invertebrates (bryozoans, ascidians, soft corals, tunicates) from the Indo-Pacific and eastern Pacific regions. Sediments provide a rich source of diverse actinomycetes that are yielding new biological activities and natural products. Based on our findings that novel classes of microorganisms that produce important secondary metabolites are being discovered from marine sources, there is exciting new information to be learned from these novel organisms at the genetic, biochemical and metabolomic levels. Talented undergraduate students are trained to acquire a diverse set of microbiology skills that include developing new conditions and media for growing diverse forms of marine bacteria. As pure cultures are obtained, their research experience develops to include phylogenetic analysis of the microorganisms using 16S rRNA gene sequence analysis, total genome sequencing, biosynthetic gene cluster mining, and bioinformatics analysis. In addition, students that are interested in chemical aspects of microbiology participate in large scale culture, extraction, fractionation and purification of biologically active natural products. We also have an active program in biocatalysis discovery, characterization and enzyme characterization.

Peter Tessier
Faculty Profile
Lab Website

Project Title:  Bioinformatics and computational methods for improving antibody discovery
Project Description: 
The success of therapeutic antibodies depends not only on their specific bioactivities but also on their highly variable and difficult-to-predict physicochemical properties (solubility, specificity and biodistribution). The goals of this project are to develop predictive computational and bioinformatics methods for designing, optimizing and identifying drug-like monoclonal antibodies for therapeutic and diagnostic applications. Interested candidates should have experience in programming, and an interest in biotechnology. 

Alternate Project Title:  Novel methods for discovering antibodies and antibody-like molecules
Project Description: 
In vitro methods such as phage and yeast surface display are commonly used for screening large antibody libraries to identify rare variants with high affinity and specificity. However, there are several key challenges related to in vitro antibody discovery that must be solved to improve the utility and robustness of these methods. The goals of this project are to i) generate novel antibody libraries that closely resemble those generated by the natural immune system, ii) develop novel screening methods for identifying drug-like antibodies with high specificity and solubility, iii) identify conformation-specific antibodies specific for several complex target molecules, and iii) identify agonist antibodies that activate cellular receptors. Interested candidates should have an interest in biotechnology.

Raymond Trievel
Faculty Profile

Project Title:  Structure and Function of Histone Modifying Enzymes
Project Description:
Genomic DNA in eukaryotes is organized in a hierarchical structure termed chromatin. Nucleosomes represent the basic repeating unit in chromatin and are composed of an octamer of the core histones H2A, H2B, H3, and H4, around which is wrapped DNA. Histones undergo a plethora of posttranslational modifications, such as methylation, phosphorylation, ubiquitination and various forms of acylation. These modifications have fundamental roles in governing a diverse array of nuclear processes, including transcription, epigenetic silencing, chromatin remodeling, DNA damage response, and maintenance of genome stability. Histone modifying enzymes catalyze the addition or removal of these modifications to dynamically regulate these processes. Dysregulation of the activities of histone modifying enzymes has been implicated in numerous types of cancer, neurogenerative disorders, bacterial pathogenesis, and other diseases. Our laboratory focuses on studying the substrate specificities, catalytic mechanisms, and regulation of histone lysine methyltransferases and demethylases employing biochemical and biophysical methods. Students engaged in research in our lab will receive training in techniques such as molecular biology, protein expression and purification, X-ray crystallography, enzyme kinetics, calorimetry, and fluorescence-based binding assays, providing an interdisciplinary research experience in chromatin biochemistry.

Ashootosh Tripathi
Faculty Profile
Lab Website

Project Title: Rational Data-Based Natural Product Drug Discovery
Project Description:
The efforts of the Natural Products Discovery Core is to isolate novel marine bacteria from all over the world and develop a data-intensive NP drug discovery platform. Based on our findings that novel classes of microorganisms that produce important secondary metabolites are being discovered from marine sources, there is exciting new information to be learned from these novel organisms at the genetic, biochemical, and metabolomic levels. Talented undergraduate students are trained to acquire a diverse set of microbiology skills that include developing new conditions and media for growing diverse forms of marine bacteria. As pure cultures are obtained, their research experience develops to include chromatographic separation, mass spectrometry data collection, and analysis of microbial metabolites, phylogenetic analysis of the microorganisms using 16S rRNA gene sequence analysis, total genome sequencing, biosynthetic gene cluster mining, and bioinformatics analysis. In addition, students that are interested in chemical aspects of microbiology participate in large-scale culture, extraction, fractionation, and purification of biologically active natural products. We also have an active program in biocatalysis discovery, characterization, and enzyme characterization.

Qiong Yang
Faculty Profile
Lab Website

Project Title: Biophysics of Living Systems
Project Description:
Our lab employs interdisciplinary approaches (imaging, microfluidics, modeling) for a quantitative understanding of self-organizing behaviors of single cells and single molecules during early embryo development. By connecting the understanding at the molecule, cellular, and tissue levels, we pin down the physical mechanisms that give rise to collective spatiotemporal patterns that arise from complex interactive networks of cells and molecules through biochemical signals and mechanical forces. 

Two potential REU projects this year:

For the ongoing tunability project: Understanding the tunability of oscillators through modeling. Certain biological oscillators like the cell cycle can vary their period over a large range. Others, such as the circadian oscillator, maintain a robust period against perturbations. This project combines differential equations, sensitivity analysis, bifurcation diagrams, and protein interaction networks to understand which biological circuits are more tunable in period and amplitude. 

For the model discovery project: Data-driven discovery of dynamical models. Recent advances in machine learning and sparsity-promoting techniques such as SINDy, show promise as tools for the discovery of dynamical equations that govern biological systems. The quality and quantity of data generated in our lab present a unique opportunity to test these novel techniques with experimental data. This project aims to test these techniques and compare the results with well-established models of biological oscillators.