Please review the REU projects and research interests of the REU faculty mentors listed below. Select five faculty members with whom you would like to work. There is no guarantee that you will be matched with your top choice, if selected for participation in the program, but every attempt will be made to accommodate your interests.
Please note that all projects will be adapted for completion virtually. If not stated below, these adaptations may involve extensive data analysis, computational modeling, data mining, genomic analysis, computational simulations, literature reviews, etc.
Laptop computers, with the necessary software/hardware, will be provided for use during the program.
- Charles L. Brooks III (Chemistry & Biophysics) - In Silico Drug Discovery and Development
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 and python is suggested, but not required, as students will learn how to work in our environment from other team members through structured mentoring. This project will be run virtually as a result of the pandemic. The student working in the project will meet weekly with the PI and will have a graduate student mentor to ensure good progress can occur in the REU project.
- Heather Carlson (Medicinal Chemistry) - Computational Studies of Protein-Ligand Binding
Project Title: Computational Studies of Protein-Ligand Binding
Cosolvent molecular dynamics simulations use small organic probe molecules to sample along a protein surface and identify binding "hotspots." The benefits of this approach are that the protein can adapt to the presence of the cosolvents and the cosolvents must compete with water to interact with the protein. Accommodating protein flexibility and hydration effects are two leading challenges in structure-based drug discovery. Advances in cosolvent molecular dynamics will be pursued including applications to allosteric systems, assessment of fragment binding, identification of cryptic binding sites, and prediction of target druggability. Though these approaches require significant computational resources, they have the promise of identifying previously unknown regulatory sites on proteins, which could significantly increase the number of drug targets available to treat a wide variety of medical disorders.
- Timothy Cernak (Medicinal Chemistry) - Chemical synthesis at the interface of data science
Project Title: Chemical synthesis at the interface of data science (www.cernaklab.com)
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 (Cell and Developmental Biology) - Understanding the proteins important for Membrane traffic
Project Title: Understanding the proteins important for Membrane traffic
Automated approaches to image analysis and other data processing steps are rapidly becoming the norm in biomedical and biological research. The available project will focus on developing these skills in a remote-learning research experience to understand how protein-protein interactions contribute to the process of membrane traffic. Students working with us will perform data analysis to contribute to our ongoing work understanding clathrin mediated membrane traffic. Approaches may include developing analytical pipelines to automate image analysis in CellProfiler, analyzing existing microscopy data, using online tools to explore co-evolution of proteins, using online tools to predict protein structure and designing molecular biology pipelines to produce constructs for ongoing work in the lab. No prior experience in computer programming is required.
- Roland Kersten (Medicinal Chemistry) - Computational exploration of plants for new cyclic peptide natural products
Project Title: Computational exploration of plants for new cyclic peptide natural products
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 by prediction of new natural products from plant genes encoded in plant genomes and transcriptomes. This project aims to characterize new plant peptide natural products from diverse plants based on computational analysis of plant biosynthetic genes and subsequent metabolomic analysis of plants with predicted peptide chemistry. 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. In this project, a database of >1000 plant transcriptomes will be searched computationally for peptide cyclase genes underlying the production of cyclic plant peptides. Candidate cyclase genes will then be analyzed for structural information of the corresponding peptide natural products to enable a prediction of new peptide structures from a given plant transcriptome. Plants with promising peptide predictions will then be purchased or collected in the University of Michigan botanical garden or Herbarium and analyzed by mass spectrometry-based metabolomics in their tissues (root, leaf, stem, flower) for the predicted natural products. For newly identified peptides, peptide cyclase genes will be purchased as synthetic genes 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 transcriptomics, plant metabolomics and plant synthetic biology approaches remotely. Chemical experiments such as target plant collection and extraction and heterologous gene expression in tobacco will be conducted by Kersten lab members to assist a virtual exploration of plant peptide chemistry. The results of the project will broaden our knowledge of peptide chemistry in the plant world and guide future natural product discovery.
- Cora MacAlister (Molecular, Cellular, and Developmental Biology) - The localization and dynamics of extracellular matrix proteins in tomato fertilization
Project Title: The evolution of a specialized glycosyltransferase in the Solanaceae (Nightshade) family of flowering plants
Project Description: The Solanaceae family of flowering plants contains many economically important plants including tomato, potato, bell and chili peppers, petunia, tobacco, eggplant and tomatillo. The production of many crop plants, including tomato, requires successful fertilization to trigger seed and fruit development. Fertilization in flowering plants relies on pollen to deliver sperm cells to ovules protected deep within the flower. However, the molecular basis of sexual reproduction, particularly in crop plants, is poorly understood. We have recently identified a hydroxyproline o-arabinosyltransferase (HPAT) that is required for tomato pollen fertility. HPATs are deeply conserved in the land plants and green algae and modify many proteins, particularly cell wall-associated proteins, by catalyzing the addition of an arabinose sugar onto specific hydroxyproline residues. Plants carrying a mutation in one of the tomato HPAT genes have disrupted pollen cell walls, leading to physically weaker pollen and poor pollen fertility. Interestingly, this gene is the result of a recent duplication occurring at some point in the evolution of domesticated tomato. Unlike other members of HPAT gene family, this gene is only expressed in anthers (the floral organ which produces pollen) and in pollen itself, suggesting it has become specialized for pollen development. Other HPATs are generally expressed in most or all plant tissues and likely have a general, housekeeping function. While this pollen-specialized HPAT occurs in tomato, it is absent from other, well studied plants (e.g. Arabidopsis thaliana). When, during the evolution of the tomato lineage, did this gene appear and when did it become specialized for pollen development? This project will use bioinformatics to identify HPAT genes in the available genome and transcriptome data for other members of the Solanaceae family, build a phylogeny of the HPAT gene family in these species, design specific primers to test the expression of these genes across tissues, and analyzing the resulting data.
- Anna Mapp (Chemistry) - Towards a Molecular-Level Picture of Gene Transcription
Project Title: Towards a Molecular-Level Picture of Gene Transcription
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 (Pharmaceutical Sciences) - ImmuoEngineering
Project Title: ImmuoEngineering
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. In our studies, we employ 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. In this year’s project, REU student will help us analyze the biological dataset obtained from these studies to understand how the host’s immune system responds to drug therapies.
- Zaneta Nikolovska-Coleska (Pathology) - Towards Developing Molecularly Targeted Small Molecule Inhibitors
Project Title: Towards Developing Molecularly Targeted Small Molecule Inhibitors
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 (Biological Chemistry) - Molecular Mechanisms of DNA Repair
Project Title: Molecular Mechanisms of DNA Repair
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. Remote research will involve participating in group meetings, reading papers and discussing them in journal clubs. Independent projects suited to remote research setting include modeling enzymatic reactions, exploring evolutionary relationships between DNA repair pathways in different kingdoms of life, and evaluating rare gene variants for possible disease associations.
- Stephen Ragsdale (Biological Chemistry) - Role of Metal-Containing Cofactors in Biochemistry
Project Title: Role of Metal-Containing Cofactors in Biochemistry
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 (Biological Chemistry) - Reverse engineering epigenetic memory in eukaryotic cells
Project Title: Reverse engineering epigenetic memory in eukaryotic cells
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.
All projects will be virtual.
Examples of lab-based 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 (Pharmaceutical Sciences) - Quantitative analysis of Drug Transport
Project Title: Quantitative analysis of Drug Transport
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 will be involved in computational research projects involving data mining of public databases for information related to the physicochemical properties of the molecules and their subcellular distribution, and integrating this knowledge with other projects in the lab to design molecules that are targeted to accumulate in specific sites of action in the organism while avoiding unwanted accumulation in off-target sites.
- Les Satin (Pharmacology) - Role of Metabolism in Insulin Secretion Oscillations
Project Title: Role of Metabolism in Insulin Secretion Oscillations
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.
During the Covid-19 pandemic we have supported virtual projects involving calculations, mathematical simulations, data analysis methods and their application to our experimental data and teaching of experimental methodologies. Projects involving review of the research literature and producing short review articles are an additional possibility.
- Anna Schwendeman (Pharmaceutical Sciences) - Optimization of HDL Nanomedicines for Treatment of Heart Disease
Project Title: Optimization of HDL Nanomedicines for Treatment of Heart Disease
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 (Medicinal Chemistry) - Marine Microbial Discovery and Analysis
Project Title: Marine Microbial Discovery and Analysis
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, it is clear that there is exciting new information to be learned from these novel organisms at the genetic and biochemical 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, cell wall composition and fatty acid analysis, menaquinone characterization and genome fingerprinting (RFLP analysis). In addition, those students that are interested in chemical aspects of microbiology participate in large scale culture, extraction, fractionation and purification of biologically active natural products. Virtual projects are possible and will be related to genome analysis of our microbial repository now underway using PacBio sequencing.