Research in our laboratory focuses on a class of intracellular ion channels know as ryanodine receptors (RyRs). In mammals, there are three RyR isoforms. RyR1 and RyR2 are the predominate isoforms in skeletal and cardiac muscle, respectively where they are the primary efflux pathway for the release of calcium from the sarcoplasmic reticulum to activate contraction. RyR3 has a wide tissue distribution and contributes to calcium regulation in a variety of cell types. RyRs are the largest known ion channel and are regulated by a multitude of endogenous effectors, including ions, metabolites and regulatory proteins. Therefore, an area of interest is the regulation of these RyR channels by endogenous effectors; especially as it relates to altered contractile function associated with cardiac and skeletal disease, skeletal muscle fatigue and aging. We analyze channel function on multiples levels of organization. Sarcoplasmic reticulum vesicle [3H]ryanodine binding is used to examine large populations of channels. Individual channels are incorporated into artificial lipid bilayers in order to record single channel currents and assess channel kinetics. Calcium release from permeabilized muscle fibers provides a method of examining RyR function in situ. My research has two long-range goals. The first is to understand how intracellular calcium is regulated and how alterations in the regulation effects cell function. The second goal is to understand the RyR regulatory sites that could potentially be exploited for the development of pharmacological compounds to treat disorders of cellular calcium regulation.
Our laboratory has diverse research interests including: evolutionary synthetic biology, molecular biology, comparative genomics, computational biology, bioinformatics, biomedicine, molecular evolution and origins of life, and evolution and engineering of protein thermostability.
Quantitative Evolutionary Genetics. After 15 years working on genomic approaches to complex traits in Drosophila, my group has spent much of the past 10 years focusing on human quantitative genetics. We start with the conviction that genotype-by-environment and genotype-by-genotype interactions are important influences at the individual level (even though they are almost impossible to detect at the population level). We use a combination of simulation studies and integrative genomics approaches to study phenomena such as cryptic genetic variation (context-dependent genetic effects) and canalization (evolved robustness) with the main focus currently on disease susceptibility.
Immuno-Transcriptomics. As one of the early developers of statistical approaches to analysis of gene expression data, we have a long-term interest in applications of transcriptomics in ecology, evolution, and lately disease progression. Since blood is the most accessible human tissue, we’ve examined how variation is distributed within and among populations, across inflammatory and auto-immune states, and asked how it relates to variation in immune cell types. Our axes-of-variation framework provides a new way of monitoring lymphocyte, neutrophil, monocyte and reticulocyte profiles from whole peripheral blood. Most recently we have also been collaborating on numerous studies of specific tissues or purified cell types in relation to such diseases as malaria, inflammatory bowel disease, juvenile arthritis, lupus, and coronary artery disease.
Predictive Health Genomics. Personalized genomic medicine can be divided into two domains: precision medicine and predictive health. We have been particularly interested in the latter, asking how environmental exposures and gene expression, metabolomic and microbial metagenomics profiles can be integrated with genome sequencing or genotyping to generate health risk assessments. A future direction is incorporation of electronic health records into genomic analyses of predictive health. Right now it is easier to predict the weather ten years in advance than loss of well-being, but we presume that preventative medicine is a big part of the future of healthcare.
All organisms use chemicals to assess their environment and to communicate with others. Chemical cues for defense, mating, habitat selection, and food tracking are crucial, widespread, and structurally and functionally diverse. Yet our knowledge of chemical signaling is patchy, especially in marine environments. In our research we ask, "How do marine organisms use chemicals to solve critical problems of competition, disease, predation, and reproduction?" Our group uses an integrated approach to understand how chemical cues function in ecological interactions, working from molecular to community levels. We also use ecological insights to guide discovery of novel pharmaceuticals and molecular probes.
In collaboration with other scientists, our most significant scientific achievements to date are: 1) characterizing the unusual molecular structures of antimicrobial defenses that protect algae from pathogens and which show promise to treat human disease; 2) understanding that competition among single-celled algae (phytoplankton) is mediated by a complex interplay of chemical cues that affect harmful algal bloom dynamics; 3) unraveling the molecular modes of action of antimalarial natural products towards developing new treatments for drug-resistant infectious disease; 4) discovering that progesterone signaling and quorum sensing are key pathways in the alternating sexual and asexual reproductive strategy of microscopic invertebrate rotifers - animals whose evolutionary history was previously thought to preclude either cooperative behavior (quorum sensing) typically associated with bacteria and hormonal regulation via progesterone typically seen in vertebrates; 5) identifying a novel aversive chemoreception pathway in predatory fish that results in rapid recognition and rejection of chemically defended foods, thereby protecting these foods (prey) from predators.
Ongoing projects include: 1) Waterborne chemical cues in the marine plankton: a systems biology approach (including metabolomics); 2) Exploration, conservation, and development of marine biodiversity in Fiji and the Solomon Islands (including drug discovery, mechanisms of action, and chemical ecology); 3) The role of sensory environment and predator chemical signal properties in determining non-consumptive effect strength in cascading interactions on oyster reefs; 4) Regulation of red tide toxicity by chemical cues from marine zooplankton; 5) Chemoreception of prey chemical defenses on tropical coral reefs.
Most biological traits have a strong genetic, or heritable, component. Understanding how genetic variation influences these phenotypes will be important for understanding common, heritable diseases like autism. However, the genetic architecture controlling most biological traits is incredibly complex – hundreds of interacting genes and variants combine in unknown ways to create phenotype. The McGrath lab is interested in using fundamental mechanistic studies in C. elegans to identify, predict, and understand how genetic variation impacts the function of the nervous system. We are studying laboratory adapted strains and harnessing directed evolution experiments to understand how genetic changes affect development, reproduction, and lifespan. We combine quantitative genetics, CRISPR/Cas9, genomics, and computational approaches to address these questions. We believe this work will lead to insights into evolution, multigenic disease, and systems biology.
Focused on the study of aquatic chemical ecology, Dr. Jeannette Yen’s lab employs graduate and undergraduate students alike in the pursuit of understanding marine zooplankton interaction, behavior, morphology, ecology and reproductive strategies. Current research topics range from the study of harmful algal blooms effect on marine copepod behavior to understanding the swimming behavior and hydrodynamics.
Neuroscience, biomechanics, neural control of movement, locomotion, reaching rehabilitation
The major research focus of my research is on biomechanics and motor control of locomotion and reaching movements in normal as well as in neurological and musculoskeletal pathological conditions. In particular, we study the mechanisms of sensorimotor adaptation to novel motor task requirements caused by visual impairament, peripheral nerve or spinal cord injury, and amputation. We also investigate how motor practice and sensory information affect selections of adaptive motor strategies.
Structure and function of eukaryotic membrane proteins, two-dimensional crystallization, electron crystallography, electron cryo-microscopy (cryo-EM)
Eukaryotic membrane proteins comprise approximately 60% of all drug targets and are consequently immensely important for biomedical research. Despite their importance, only few could thus far be studied at the structural level. My research focuses on the crystallization, structure and function of eukaryotic membrane proteins.
Electron crystallography is the main tool employed to study these proteins in my laboratory. Initially, this involves testing of conditions for growing two-dimensional (2D) crystals, usually by reconstituting the detergent-solubilized membrane protein into a bilayer. Once crystallization parameters have been identified by electron microscopy of negatively stained samples, electron cryo-microscopy is employed to collect high-resolution data. The structure is then obtained by image processing.
The approach of 2D crystallization and electron crystallography is particularly suitable for highly fragile membrane proteins such as many eukaryotic ones. Reconstitution ensures an environment that is close to the native one, the detergent is removed, and functional studies are relatively easily undertaken. Experimental phases are obtained due to the fact that images are collected. In some instances the image amplitudes can be substituted with electron diffraction amplitudes.
Although electron crystallographic methods are well developed, little is known about the factors important in 2D crystallization, and screening protocols as for 3D crystallization do not exist. An important aspect of my research interests aims at developing screening methods and strategies for 2D crystallization and at understanding the underlying mechanisms.
Post-translational modifications, protein mass spectrometry, cell signaling
My lab integrates mass spectrometry and experimental cell biology using the yeast model system to understand how networks of coordinated PTMs modulate biological function. Now well into the era of genomics and proteomics, it is widely appreciated that understanding individual genes or proteins, although necessary, is often not sufficient to explain the complex behavior observed in living organisms. Indeed, placing context on the dynamic network of relationships that exist between multiple proteins is now one of the greatest challenges in Biology. Post-translational modifications (PTMs, e.g. phosphorylation, ubiquitination and over 200 others), which can be readily quantified by mass spectrometry (MS), often mediate these dynamic relationships through enhancement or disruption of binding and/or catalytic properties that can result in changes in protein specificity, stability, or cellular localization. We use a combination of tools including quantitative mass spectrometry, yeast genetics, dose-response assays, in vitro biochemistry, and microscopy to explore testable systems-level hypotheses. My current research interests can be grouped into four main categories: (1) coordinated PTM-based regulation of dynamic signaling complexes, (2) cross-pathway coordination by PTMs, (3) PTM networks in stress adaptation, and (4) technology development for rapid PTM network detection.