The Cognitive Motor Control Laboratory seeks to understand neurophysiology guiding skillful human-object interactions in upper extremity motor control. We use neuroimaging to identify anatomical and physiological circuits in humans that guide successful skilled behavior. Our clinical studies consider neural systems that can suffer injury or dysfunction related to deficits in skillful motor control, and how to utilize surrogate neural circuits in restorative motor therapies in stroke and upper limb amputation.
We seek to answer how animal behavior is set up by the collective behaviors of individual cells, over the entire course of brain and spinal cord development. We want to understand how gene activity can instruct developing neurons to move around, change shape, and connect to other cells. To do this, we study the simple larval nervous system of our closest invertebrate relatives, the tunicates. Tunicates, like us, belong to the Chordate phylum, but have very simple embryos and compact genomes. The laboratory model tunicate Ciona has only 177 neurons and is the only chordate with a fully mapped "connectome". We take advantage of this simplicity to understand molecular mechanisms that may underlie human neurodevelopment.
Current research is directed at understanding the origin and evolution of RNA assemblies and activities that gave rise to RNA-based genetic and metabolic systems, and the interaction of a bacterial RNA-binding protein Hfq that is crucial for the regulation of gene expression by short regulatory RNAs.
The first research area is examining the assembly and activities of RNA under plausible early earth conditions ( e.g. anoxic environment, freeze-thaw cycles of aqueous solutions). We have shown that Fe2+can replace Mg2+ and enhance ribozyme function under anoxic conditions. Fe2+ was abundant on early earth and may have enhanced RNA activities in an anoxic environments. Freeze-thaw cycles can also promote RNA assembly under conditions where degradation is minimized.
The second area of research is investigating the mechanism of the Hfq protein. Hfq is a bacterial RNA-binding protein that facilitates the hybridization of short non-coding regulatory RNAs (sRNA)to their target regions on specific mRNAs. sRNAs are important elements in the regulation of gene expression for bacteria.Hfq is highly conserved among bacterial phyla and has been shown to be a virulence factor in several bacterial species. The interactions of wild type and mutant Hfq proteins with various RNAs are examined using biochemical/ biophysical methods such as the electrophoresis mobility shift assay, fluorescence spectroscopy, and mass spectrometry.
The work in this laboratory is focused on mechanisms underlying motor coordination in mammalian systems. These mechanisms are to be found in the structure and dynamic properties of the musculoskeletal system as well as in the organization of neuronal circuits in the central nervous system. Our work concerns the interactions between the musculoskeletal system and spinal cord that give rise to normal and abnormal movement and posture, and in the manner in which central pattern-generating networks are modified for specific motor tasks. Our studies have applications in several movement
disorders, including spinal cord injury. The experimental approaches span a number of levels, from mechanical studies of isolated muscle cells to kinematic measurements of natural behavior in quadrupeds.
Microbiology, quorum sensing, regulatory small RNAs, signal transduction, host-pathogen interactions, microbial biofilms.
Our lab studies molecular mechanisms important for microbial interactions. Bacteria are genetically encoded with regulatory networks to integrate external information that tailors gene expression to particular niches. Bacteria use chemical signals to orchestrate behaviors that facilitate both cooperation and conflict with members of the communities they inhabit. We use genetics and genomics, biochemistry, bioinformatics, and ecological approaches with a focus on the waterborne pathogen Vibrio cholerae.
Sphingolipid Metabolism & Cell Regulation, Lipidomics & Systems Biology, Tissue Imaging Mass Spectrometry, Macrophage Biology, Lipid Signaling in Disease, especially Cancer
Yeast genetics and molecular biology, chaperones and protein misfolding, amyloid and prion diseases, epigenetics and protein-based inheritance.
My laboratory employs yeast models to study prions and amyloids. Prions were initially identified as proteins in an unusual conformation that cause infectious neurodegenerative diseases, such as "mad cow" disease, kuru or Creutzfeldt-Jakob disease. Infection depends on the prion's ability to convert anon-prion protein, encoded by the same host maintenance gene, into the prion conformation. Prions form ordered cross-beta fibrous aggregates, termed amyloids. A variety of human diseases, includingAlzheimer's disease, are associated with amyloids and possess at least some prion properties. Someamyloids have positive biological functions. Many proteins can form amyloids in specific conditions. It is thought that amyloid represents one of the ancient types of the protein fold. Some yeast non-Mendelianheritable elements are based on a prion mechanism. This shows that heritable information can be coded in protein structures, in addition to information coded in DNA sequence. Therefore, prions provide a basis for the protein-based inheritance in yeast (and possibly in other organisms).
Major topics of research in my lab include cellular control of prion formation and propagation (with a specific emphasis on the role of chaperone proteins), and development of the yeast models for studying mammalian and human amyloids, involved in diseases. Our research has demonstrated that prions can be induced by transient protein overproduction and discovered the crucial role of chaperones in prionpropagation, shown evolutionary conservation of prion-forming properties, established a yeast system for studying species-specificity of prion transmission, and uncovered links between prions, cytoskeletalnetworks and protein quality control pathways.
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.
We are broadly interested in evolutionary genomics and epigenomics problems and have never been afraid to take up a new topic. Here are some of our current research interests.
Epigenetic Evolution of human Brains: A major research thrust in the lab is to understand how epigenetic regulatory mechanisms evolve. One specific question is how DNA methylation patterns in human brains have evolved since humans and chimpanzees have diverged. Human brains are arguably one of the most exceptionally rapidly evolved organ in the human body. We have published a few articles on this, and hopefully many more to come.
Neuroepigenomics: We are also interested in understanding how epigenetic marks regulate and/or propagate neuropsychiatric diseases of human brains. Our current research include epigenetic analysis of schizophrenia brains.
Epigenetics and Genome Evolution: Epigenetic mechanisms are widespread throughout the tree of life, but its components and how each component interact with each other vary greatly across different taxa. For example, genomic patterns of DNA methylation in invertebrate animals differ greatly from those of vertebrates. We have been studying how DNA methylation in invertebrates vary across the genome and among species, and how epigenetic variation yields functional consequences.
Linking genomes and phenotypes in a vertebrate model system: In collaboration with Dr. Donna Maney at Emory University, we are investigating how a prevalent chromosomal polymorphism in the white-throated sparrow leads to two distinctive and complex phenotypes. We use genomic and epigenomic tools to complement the behavioral and physiological approaches of our collaborators.
