We use the powerful model genetic organism, C. elegans, to discover new conserved aspects about muscle assembly, maintenance and regulation. Although our work is basic science, it has relevance to human diseases of muscle including cardiomyopathies and muscular dystrophies. Our main projects are: (1) The structures and functions of giant polypeptides in muscle, >700,000 Da, that consist of multiple Ig and Fn domains and one or two protein kinase domains. One focus is to determine the substrates for these kinases, and how they are activated (normally autoinhibited). The problem of activation is being studied in collaboration with structural biologist Olga Mayans (Univ. of Konstanz) and biomedical engineer Hang Lu (Georgia Tech). Recently, we have discovered that UNC-89 (human “obscurin”) kinase activity is required for proper mitochondrial organization and function. This has initiated a collaboration with Jennifer Kwong in Emory’s Pediatrics Dept. (2) The molecular mechanism by which the muscle contractile units (sarcomeres) are attached to the muscle cell membrane and transmit force. This involves “integrin adhesion complexes” (IACs) consisting of the trans-membrane protein integrin and many other proteins. C. elegans muscle has 3 such IACs, and through a mutant screen, we discovered a conserved protein (a GEF for Rac) that directs assembly specifically at one of these sites. (3) In collaboration with biophysicist Andres Oberhauser (UTMB), we are studying the mechanisms by which the conserved myosin head chaperone, UNC-45 folds or re-folds myosin heads, and we have recently discovered a role for UNC-45 in muscle aging (sarcopenia). This project has also branched into a screen for small compounds that increase the expression of UNC-45 and reduce sarcopenia. (4) We have a long-term collaboration with Dan Kalman in Emory’s Pathology Dept. to study the beneficial effects of small molecules produced by the gut microbiome that promote healthspan, especially the attenuation of sarcopenia.
The goal of my research is to develop a method for mapping spontaneous activity throughout the whole brain with high spatial and temporal resolution, with the intention of using this technique to characterize alterations in dynamic neural activity linked to dysfunction and to identify potential targets for intervention. My primary expertise is in fMRI and functional connectivity mapping, and since my lab was established at Emory, we have focused on obtaining information about the dynamic activity of functional networks from the BOLD signal. Despite BOLD’s indirect relationship to neural signals, evidence is growing that the BOLD fluctuations provide information about behaviorally relevant network activity. We take a two-pronged approach to the problem, combining MRI with direct neural measures like electrophysiology and optical imaging in the rodent, or with EEG and behavioral outputs in the human. Our effort to understand the relationship between BOLD and electrical or optical recordings (very different signals that cover very different spatial and temporal scales) has led us to develop new approaches to data analysis that include spectral, spatial, and temporal information. To better understand the large-scale dynamics of brain activity, we have become fluent in network modeling, nonlinear dynamics, and machine learning.
Adam M. Klein, MD, FACS joined the Emory Voice Center in the Emory Department of Otolaryngology in 2005 after completing a fellowship in Laryngology and Care of the Professional Voice at the Harvard University for Laryngeal Surgery and Voice Restoration. His research interests include vocal fold reanimation, recurrent respiratory papillomatosis, neurologic disorders of the voice and surgical simulation. He has been issued US patents for Apparatuses and Methods for Simulating Microlaryngeal Surgery and Surgical Arm Support for Phonomicrosurgery, with others pending.
As an innovator of new surgical and simulation devices, Dr. Klein has worked to build a culture of collaboration between his department and the Georgia Institute of Technology. He serves as a faculty mentor for the Masters in Biomedical Innovation and Development program, as well as numerous senior design projects. He created and directs the Emory Innovation Group in Otolaryngology and lectures nationally and internationally on new innovations and treatments in the management of voice disorders.
Medical and Surgical Device Design, Development and Delivery
childhood cancer, leukemia, cancer predisposition, cancer immunology
The goal of the Porter lab is to develop novel therapeutic strategies for leukemia through better understanding of molecular mechanisms of leukemogenesis and treatment resistance. We employ a wide variety of techniques, in vitro and in vivo, for discovery and validation of molecular vulnerabilities in cancer cells. For example, using a genome-scale shRNA screen, we identified WEE1 as a chemosensitizing target in AML cells. Subsequent studies funded by the NCI have validated this finding and supported the development of a clinical trial testing a WEE1 inhibitor in children with relapsed/refractory AML. More recently, we have discovered a novel function for the transcription factor ETV6 in regulating normal B cell development, and will test whether and how Etv6 mutation promotes leukemogenesis using a new mouse model with a point mutation in Etv6. A third project in the lab is directed at understanding mechanisms of immune evasion during leukemogenesis.
Craniofacial muscles are essential muscles for normal daily life. They are involved in facial expressions (facial muscles), blinking and eye movement (eye muscles), as well as speaking and eating (tongue and pharyngeal muscles).
Interestingly, craniofacial muscles have differential susceptibility to several muscular dystrophies. For example, craniofacial muscles are the most affected muscles in oculopharyngeal muscular dystrophy but the least affected muscles in Duchenne muscular dystrophy. Among craniofacial muscles, dysfunction of tongue and pharyngeal muscles could cause an eating disability, called dysphagia, afflicts almost 15 million Americans including elderly, neuronal (Parkinson’s disease and bulbar-onset amyotrophic lateral sclerosis) and muscular disease (oculopharyngeal muscular dystrophy) patients. However, no cure or therapeutic treatment exists for dysphagia caused by muscular dystrophy. Elucidation of the mechanism(s) behind these differing susceptibilities of craniofacial muscles could lead to development of potential therapeutics targeted to specific skeletal muscles involved in particular types of muscular dystrophy.
The mechanisms of skeletal muscles are of interest here because skeletal muscle cells are multinucleated cells. Typically, skeletal muscle cells contain hundreds of nuclei in a single cell since they are generated by fusion of muscle precursor cells during development or by fusion of muscle specific stem cells, called satellite cells, in adult skeletal muscles. However, it is unclear how skeletal muscle cells regulate the quantity and quality of these multi-nuclei. Since craniofacial skeletal muscles, such as extraocular and pharyngeal muscles, have active satellite cell fusion in comparison to limb muscles, they are therefore suitable models to study myonuclear addition and homeostasis.