Abnormal synaptic changes contribute to the majority of neurological diseases.
Focusing on the auditory system, Dr. Bao’s research group has been studying whether two ‘opposite disorders’, hearing loss and tinnitus, are both the result of abnormal synaptic changes that occur due to aging or early noise exposure. This group has been working to understand basic cellular and molecular mechanisms underlying these abnormal changes, employing a variety of molecular, behavioral, electrophysiological, and imaging methods. At the same time, the group has also explored translational opportunities to treat these disorders with pharmacogenomic approaches and stem cell therapies. Recently, the group discovered an effective means for eliminating or delaying hearing loss with drugs that are already approved by the U.S. Food and Drug Administration (FDA) for other indications. With funding from both the National Institutes of Health (NIH) and other sources, the group continues to explore basic mechanisms underlying these age-related disorders and other sources, the group continues to explore basic mechanisms underlying these age-related disorders and simultaneously develop both drug and stem cell therapies to treat these common diseases.
Based on recent seminal preclinical studies from Dr. Bao’s research group showing that antiepileptic drugs that block calcium channels effectively diminish presbycusis, a collaborative research project has been established to test whether the severity of age-related hearing loss is correlated with specific genetic variants in genes encoded for calcium signaling as well as whether causal genetic variants in the same genes associated with better hearing can be determined in elderly persons taking calcium channel blockers. The long-term goal of this project is to develop a personalized medical intervention for presbycusis. The innovative aspect of this study is to apply pharmacogenetic approaches to discover personalized medications to prevent presbycusis.
In addition to Dr. Bao’s research group, a multidisciplinary team has been assembled that includes: Dr. Zhenyu Jia and Mike Hewit of NEOMED; Drs. Cliff Megerian, Gail Murray, and Qing Yin Zheng from Case Western Reserve University School of Medicine; and Drs. Nancy Tye-Murray and Jay F. Piccirillo from Washington University School of Medicine. This project represents a unique opportunity that brings together a diverse team for the purpose of conducting translation research to improve health outcomes of patients at risk for presbycusis.
The Cooper lab is externally funded and focuses on understanding the skeletal changes that occurred as mammals departed terrestrial habitats. We focus on mammals that invaded the skies, like bats, or those that invaded the seas, like whales, dolphins, and porpoises. Our research questions are aimed at understanding bone development and bone biology in general. We take a synthetic approach and integrate anatomical, biomechanical, and molecular evidence to better understand how the mammalian skeleton can be changed to allow for life in an extreme habitat. Our funded efforts focus on the mechanobiology of the bone matrix in bats, and our ongoing research investigates solutions to fragile bone disorders in humans.
Neural Mechanisms in Complex Sound Processing
We study neural mechanisms underlying complex sound processing in the auditory system of echolocating bats, which are known to have excellent hearing. At the same time many features of their sonar sounds are analogous to other communication sounds including human speech. Physiological studies in bats can therefore provide insight into how speech-like sounds are encoded in the auditory system. The major focus of our research is to examine mechanisms responsible for auditory neuron response selectivity to different parameters of complex sounds. Among different neurophysiological approaches we use in our laboratory, our primary electrophysiological technique involves intracellular recording of single auditory neurons in awake bats in response to sounds.
Behavioral impairments resulting from sensorimotor dysfunction
My research focuses on the potential interactions that exist among anatomy, neurobiology and physiology. The two broad areas of my research are (1) the functional and neurophysiologic basis of oropharyngeal function, and (2) the heterochrony and morphology of skeletal growth, with an emphasis on the evolutionary significance of these mechanisms. I am particularly interested in behavioral impairments resulting from sensorimotor dysfunction that are a significant sequela of numerous insults. Data on motor function and oropharyngeal kinematics, essential for characterizing the motor patterns, and ultimately the neural control, of feeding are virtually impossible to collect from human subjects. My lab has established a validated animal model of integrated sensory and motor function. My goals are to significantly enhance our knowledge of pathophysiology and the course of recovery, and to provide an experimental situation for testing specific rehabilitation modalities, particularly for children.
Understanding the signal transduction mechanisms/pathways that are activated by pro-inflammatory cytokines
Osteoarthritis (OA) is the most common musculoskeletal disorder in the aging population and is characterized by cartilage degradation and joint inflammation. There are currently no diseases modifying treatments and the available therapies are mostly symptomatic and the only effective treatment is surgical joint replacement. Chondrocyte is the only cell type present in the cartilage and is activated by the inflammatory cytokines interleukin-1β (IL-1b) and tumor necrosis factor-α (TNF-a) to produce matrix degrading molecules such as MMP-13, ADAMTS-5, NO, and PGE2. Using an in vitro model of human cartilage degradation we have also shown that pomegranate extract exert matrix and chondroprotective effects by suppressing the inflammatory cytokine IL-1b-induced expression of MMP-13 in human cartilage explants and chondrocytes. My research studies are focused on (1) understanding the signal transduction mechanisms/pathways that are activated by pro-inflammatory cytokines in human chondrocytes-the only cell type present in the articulating cartilage; and (2) identifying the natural products and their bioactive constituents that can block the pro-inflammatory cytokine-mediated activation of signal transduction pathways identified by us in human chondrocytes.
The second area of intense investigation in my lab is the role of microRNAs (miRNAs)-a class of non-coding RNAs regulating gene expression by sequence specific inhibition of target mRNA translation-in chondrocyte homeostatsis. Specific miRNAs has been shown to exhibit altered pattern of expression in OA and in other rheumatic diseases but their exact role in OA pathogenesis is yet to be defined.
We are also actively investigating the role of epigenetic modifications in the pathogenesis of OA and whether dietary polyphenols or compounds derived from them can interfere/reverse the epigenetic silencing of anabolic genes in OA.
We mostly use in vitro studies using discarded human cartilage samples to understand the disease pathogenesis. For in vitro studies we isolate chondrocytes from the cartilage and culture the chondrocytes in dishes and treat them with inflammatory cytokines that are known to be present in high levels in human OA joints and the natural products such as pomegranate extract. Using state-of-the-art techniques we then analyze the patterns of signal transduction and gene expression. Using UHPLC and Mass Spectrometry we characterize the natural products and identify their bioavailable constituents in blood plasma. Identified bioavailable constituents are then analyzed for their anti-inflammatory activity.
Cellular Neurophysiology of Central Auditory Neurons
Our current research interests encompass three areas 1) Functions of G-protein-coupled receptors in auditory information processing; 2) Development of neuronal properties of central auditory neurons; and 3) Cellular mechanisms underlying sound localization.
Electrophysiological (e.g. whole-cell recordings) and cell imaging approaches, combined with pharmacological tools, are employed. Our work aims to help lay the groundwork for decisions about possible therapeutic approaches to hearing defects such as tinnitus and hearing loss.
We study how the neural circuits in hearing change as we age. Age-related hearing loss is associated with a reduction in the level of GABA, a key neurochemical used to communicate among neurons throughout the auditory system. The loss of GABA leads to a variety of hearing deficits, including impairment of the ability to detect fine differences in the timing of sounds.
My laboratory identifies the auditory circuits particularly susceptible to GABA loss during aging, using complex circuit-tracing, immunohistological and imaging methods. Identifying these circuits will allow for improved therapeutic brain targets to ameliorate age-related hearing loss.
We are interested in the development of auditory perception and its underlying neural coding in the auditory system. In particular, we study how neural circuits and perceptual abilities are influenced by hearing loss and auditory experience over time. The lab examines neural activity underlying the perception of natural and artificial sounds, as well as vocal communication calls, in the Mongolian gerbil. To do so, we record from implanted arrays of electrodes in animals of different ages while they perform behavioral discrimination tasks. We use intracellular in vivo recordings to identify changes in local circuits that are associated with hearing loss and maturation. Computational analyses of the data assess alterations in neural coding that correlate with perceptual deficits and maturational changes.
Regulation of bone cell development and function, with specific emphasis on growth factors that can enhance osteogenesis
Bone loss is a major health care problem in the United States and worldwide. Risk factors associated with osteoporosis, include estrogen-deficiency (post-menopuasal) and aging. During bone development and its maintenance, the antagonistic processes of bone formation and resorption are regulated by various systemic and local factors (hormones, growth factors, cytokines, etc). It is evident that bone formation during skeletal modeling/remodeling and fracture repair requires stringent control of osteoblast proliferation and differentiation. Regulation of these biological processes involves sequential expression of cell growth and tissue specific genes in response to different regulatory signals.
Dr. Safadi’s research laboratory focuses on the regulation of bone cell development and function, with specific emphasis on growth factors that can enhance osteogenesis. We are interested in various metabolic bone diseases such as age/estrogen-induced osteopenia, osteopetrosis and cartilage-associated diseases (rheumatoid arthritis). The goal of our research is understand the pathological mechanisms underlying various bone diseases in order to develop strategies for the therapeutic management of such diseases. We identified a novel growth factor (named Osteoactivin) that has anabolic effects on bone. If we understand the mechanisms responsible for this effect, then this factor could be used as potential therapeutic agent to stimulate bone formation in diseases associated with osteopenia and increased risk of fracture.
In addition we developed an interest on the role of CNS regulation of bone mass. We are working on the role of the endocannabinoid system regulation on bone mass. We utilize the CB1 and CB2 null mice to characterize bone phenotype and examine whether conditions like Traumatic Brain Injury (TBI)-associated increase in bone mass is mediated by the endocannabinoid system.
Dr. Safadi’s laboratory is also working on another collaborative research with Dr. Mary Barbe at Temple University School of Medicine. Dr. Barbe laboratory utilizes an in vivo model for cumulative trauma disorder that focuses on the molecular and cellular mechanisms associated with tendonitis and inflammation-induced bone loss.
Functional Anatomy of the Auditory Pathways
We study brain circuits used to analyze sounds. The brain processes auditory information in ascending circuits that extend from the ear to the cerebral cortex, where sound is perceived. Descending pathways allow higher centers (e.g., cortex) to modify neural processing in the lower centers. This modification is important for many functions, such as selective attention and discrimination of sounds in a noisy environment.
Our primary subject is the guinea pig, a small mammal with well-developed hearing and well-differentiated auditory circuits. We use a variety of anatomical tracers to label specific neural pathways. We then examine these pathways in the light and electron microscopes to identify the cell types and their interconnections. We also combine these methods with immunohistochemical techniques to identify the neurotransmitters used by different circuit components.
Synaptic Transmission and Neural Circuits
We are interested in determining the criteria that sensory nuclei use to decide which incoming stimulus to enhance and which to suppress, and how a neural network maximizes the information between the input (e.g. an auditory stimulus) and the output (the neural response). The number of neurons activated by an input, the balance between excitation and inhibition, and intrinsic membrane properties and local circuitry, limit the amount of information that can be conveyed by the network about the input, and the maximization of the output becomes a complex task.
Our laboratory focuses primarily on the inferior colliculus, an auditory midbrain nucleus. The organization of the inferior colliculus and its importance to auditory function make it an excellent model system to address the functional importance of intrinsic membrane properties, synaptic transmission and network organization in controlling excitability. In particular, we are examining the characteristics of inputs and how they change with stimulus strength and frequency, and the role of voltage-gated ion channels and local circuitry in shaping neuronal responses to changing inputs.
To understand how the inferior colliculus functions, we examine the constraints imposed on response patterns by a basic circuit defined in terms of cell types and connections. Important elements of the circuit include 1) parallel excitatory and inhibitory inputs to the central nucleus of the inferior colliculus; 2) local circuitry contained within single (iso-frequency) laminae of the central nucleus; 3) inter-laminar circuitry (cross-frequency connections) within one colliculus, and 4) commissural connections between the two colliculi.
Mammalian Anatomy, Development, and Evolution
My research interests center around the evolutionary patterns associated with major morphological shifts in mammalian evolution. These patterns are the best model systems for the study of evolutionary processes because they document most directly the interaction of phylogeny, functional morphology, ontogeny, and environment. To gain as full an understanding of evolutionary shifts as possible, my research program uses data from a variety of subdisciplines, including paleontology, anatomy and embryology. Overall, my research is question-driven, I use any method that can help in unraveling relevant problems, and take advantage of emerging techniques to explore questions that were previously unanswerable.
Specific morphological shifts that I have been interested in are the origin of flight in bats and its relevance to the higher phylogeny of primates and the emergence of aquatic adaptations in whales (cetaceans). The latter is a major ongoing project, focusing on the study of those cetaceans that document the land to water transition and its developmental underpinnings as well as the adaptations of modern cetaceans. Fossil data provide direct evidence of the evolutionary transition while the analyses of modern species offer a functional and genetic framework for interpreting the fossil data.
Of special interest are the emerging adaptations of the organ systems involved with hearing, balance, locomotion, and osmoregulation, as these systems underwent dramatic change. The ultimate goal of this work is to provide a detailed account of the evolving adaptations in early whales, and to use this account to identify the constraints on cetacean evolution.
This project is large and growing and involves paleontological and sedimentological fieldwork in India, study of the embryology and development biology, the functional morphology of locomotor organs, geochemistry of dental tissues, the biophysical properties of modern dolphin earbones and phylogenetic analysis.
Evolutionary and Functional Morphology of the Mammalian Skull
My research aims to understand the relationships between the form, function and evolution of the mammalian head. Specifically, I aim to better understand how certain activities, such as chewing or biting, affect the form and evolution of the skull and face. Most of this work is question driven and falls into one of three research avenues: 1) Physiology and functional morphology, 2) Behavioral and ecological morphology and 3) Comparative morphometrics.
A major component of my research involves studying the physiology of chewing and biting. This involves using in vivo methods, such as electromyography, strain gage approaches and video analysis, to study jaw-muscle activity patterns, facial bone strains and jaw movements during chewing and biting in living animals.
A second research focus involves conducting field studies of primate chewing and biting. In addition to allowing us to assess how well our lab research mimics natural field conditions, this work provides an environmental context for interpreting morphological adaptations in the mammalian head. Recent field work includes studying the mechanics of tree gouging by common marmosets at the Estação Ecológica do Tapacurá, Brasil, studying the ecological morphology of dietary segregation among three sympatric bamboo lemurs in Ranomafana National Park, Madagascar and collecting electromyographic data during natural feeding behaviors in free-ranging howling monkeys at Hacienda La Pacifica, Costa Rica.
Finally, I am interested in comparative analyses of skull and jaw-muscle form among mammals. These comparative studies complement the lab and field research by broadly describing patterns of form-function associations and morphological integration among species and/or age-groups.
Our laboratory studies neural mechanisms underlying hearing and acoustically guided behaviors, particularly social communication. We have focused increasingly on interactions between hearing and emotions. Much of our current work examines three facets of these interactions: the link between vocal signals and an animal’s emotional state, the analysis of social vocalizations by emotional centers in the brain, and the manner in which emotional centers modify processing of sounds by the auditory system. We use a wide variety of approaches in our work—acoustic, behavioral, neurophysiological, pharmacological, and anatomical. We are particularly excited about technical developments that will allow us to analyze the activity of individual neurons during social interactions. Our work on the basic neural mechanisms forms the basis for future studies of disorders of acoustic communication that involve misinterpretations of the meaning of sounds.
We thank the National Institute for Deafness and other Communication Disorders for their support of this work.
Evolutionary, comparative and developmental mechanics of terrestrial locomotion.
Research in the Young Lab focuses on evolutionary, comparative and developmental aspects of terrestrial locomotion. Much of our work is question driven and is currently concentrated on two topics: the biomechanics of arboreal locomotion, particularly in primates, and the interaction between musculoskeletal growth and locomotor development.
A principal focus of recent and past work has been the biomechanics of arboreal locomotion in primates. The aim of this work is to relate standard biomechanical measures – including gait patterns, joint postures, limb forces and center of mass movements – to fitness-critical variables such as balance, accelerative capacity and energetic efficiency. A variety of techniques are used to address this aim, including three-dimensional motion tracking, measurement of single-limb kinetics and whole-body mechanics using custom-designed force transducers, electromyography and morphometric assessments of musculoskeletal anatomy.
A second focus of our work has been the degree to which growth and development might be adaptively constrained to promote fitness across the lifespan. Immature animals must often compete against adults for resources, evade common predators and keep pace during group travel, despite small body size, an underdeveloped musculoskeletal system and other limits on performance. We should expect strong selection for mechanisms that permit young individuals to overcome such limitations and reach reproductive maturity. Previous research has examined how allometric changes in skeletal form and locomotor mechanics might facilitate improved locomotor performance in young primates. Current and future work continues to address the selective pressures operating on the interface between life history, somatic growth and locomotor development in primates and other vertebrates.