The Bird Lab is interested in how myosin molecular motors generate force on actin filaments and how defects in this fundamental cytoskeletal mechanism cause human disease. Dr. Bird studies this question using hair cells, the neural receptors for hearing and balance that are found within the inner ear. Hair cells transduce sounds and accelerations using actin-based stereocilia that protrude from their surface. The loss of stereocilia and hair cells, due to noise exposure, ototoxic drugs and aging, is a significant cause of permanent hearing impairment that is estimated to affect more than 360 million people worldwide (1).

Myosin motors are critical for hair cell sensory transduction, with mutations in no fewer than six classes of myosin genes (I, II, III, VI, VII & XV) causing hearing loss. Using a multi-disciplinary approach, the Bird Lab is investigating how myosin motors regulate molecular trafficking within stereocilia and how this ultimately controls actin dynamics and stereocilia architecture. The lab combines data from experiments with mutant animal models, cutting-edge microscopy in live cells, and purified proteins in biochemical and single molecule assays. These studies are expected to reveal the detailed mechanisms for how stereocilia mechanosensors are assembled and maintained, and they will inform the wider goal to therapeutically enhance repair processes to promote healthy, lifelong hearing.

References: http://www.who.int/mediacentre/factsheets/fs300/en/

The central hypothesis that drives the work in the Casadesus laboratory is that age-related dysregulation of fundamental physiological processes precedes and/or underlies the development of Alzheimer’s Disease (AD). Based on this hypothesis the primary aim is to identify age-related or environmentally-driven (exposome) mechanisms that underly increased AD risk (or protection). The ultimate goal is to develop novel and better targeted disease-delaying therapeutic strategies for AD.

A current major interest in the laboratory is to understand how dysregulation of specific hormones due to aging or lifestyle choices, impact neuronal structure and plasticity, cellular metabolism, and cognition. The Casadesus laboratory is also interested in identifying the genomic signatures that may explain sex-specific vulnerability or protection to these hormone changes. Particular focus is placed on understanding the roles of under-studied reproductive and metabolic hormones, their receptors, and neuroendocrine circuits. These include but are not limited to luteinizing hormone and amylin in the context of menopause and obesity/T2D.

To address such questions, the Casadesus laboratory employs a broad range of in vivo and in vitro techniques, spanning from behavioral phenotyping assays, standard biochemical measures, and confocal imaging, to systems neuroscience approaches (transcriptomics) and cutting-edge gene editing techniques using CRISPR/Cas9 and virus delivery approaches.

Olga Guryanova is an NIH-funded investigator with 15+ years of experience in translational cancer research. Her scientific career has been driven by a commitment to innovative studies into molecular mechanisms of chemotherapeutic resistance and rational strategies for cancer cell re-sensitization, with translational implications and a focus on precision oncology. After training at the Cleveland Clinic with Dr. Jeremy Rich, an expert in malignant brain tumors, she completed a postdoctoral fellowship at Memorial Sloan Kettering Cancer Center (MSKCC) under Dr. Ross Levine, a world-class authority in hematologic malignancies. Dr. Guryanova’s research has been published in top-tier journals such as Nature Medicine, Cancer Cell, and Clinical Cancer Research as a first and a senior author. She is currently an Assistant Professor and member of the University of Florida Health Cancer Center, where her laboratory is focused on delineating the mechanisms of the cross-talk between epigenetics and chromatin organization, and how these processes contribute to the development of myeloid malignancies such as acute myeloid leukemia (AML), resistance to therapies, and clonal evolution. Ultimately, Dr. Guryanova would like to harness this mechanistic understanding to develop improved therapeutic approaches for leukemia.

The Harrison Lab is interested in understanding the functional significance of chemokine networks in the central nervous system with a primary focus on determining roles for these molecules in malignant brain cancers such as glioblastoma. Dr. Harrison studies mechanisms involved in tumor-immune cell interactions as well as direct effects of chemokines on glioma initiating cells. Experimental approaches encompass in vitro and in vivo methods and include the use of chemokine receptor selective pharmacological agents.

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In many tissues, wound healing and regeneration depends on stem cells to replace the lost or damaged cells. In injured skeletal muscle, a dedicated muscle stem cell population gives rise to new muscle myofibers after an acute injury. In chronic diseases, however, muscle regeneration fails and healthy muscle is gradually replaced with fibrotic scar and fat tissue, a process called fatty fibrosis. This fatty fibrosis of muscle is a prominent feature of chronic muscle diseases such as Duchenne muscular dystrophy (DMD), sarcopenia (age-related loss of skeletal muscle and strength), obesity and diabetes. There are no cures for DMD and no specific therapies for either DMD or sarcopenia.

Coordinating cell-cell interactions is critical for regenerating complex tissues after injury or disease. Primary cilia are small, immotile, microtubule-based cell projections and have evolved to receive and interpret extracellular cues. Cilia play a crucial role in intercellular communication during development and defects in cilia lead to embryonic lethality in both mice and humans. While cilia are present on the majority of cells in our body, there’s little known about how they function or participate in the repair of adult tissues.

It was recently discovered that cilia coordinate muscle repair by controlling the communication between the muscle stem cell population and its support cells. The Kopinke Lab is now building on this work by investigating how ciliary signaling coordinates cellular communication between stem cells and their niche, to understand how cilia-based communication goes awry in disease and to identify novel pharmacological tools to combat cilia-associated diseases such as fatty fibrosis.

Some of the Law Lab’s primary research interests revolves around cyclin-dependent kinases (Cdks) in mammary tumorigenesis and chromosomal instability, and Cdk regulation by the mTOR and TGFβ pathways. This research involves the use of novel models to understand how the activation of Cdks in the mammary gland causes tumor formation by dysregulation of cell proliferation and through genetic alterations that result from chromosomal instability. These models also provide systems for testing new therapeutic strategies, including non-ATP competitive Cdk inhibitors discovered in their laboratory and for targeting the upstream signaling pathways, such as the mTOR and TGFβ axes, that stimulate Cdk kinase activity.

Other Areas of Interest

Mechanisms by which CDCP1 Promotes Breast Cancer Metastasis: The CDCP1 protein functions as a scaffold to bring together and facilitate synergy between the oncoproteins Epidermal Growth Factor Receptor (EGFR) and the Src tyrosine kinase. This results in disassembly of cell-cell and cell-substratum adhesion complexes and may facilitate cancer metastasis by permitting cancer cell invasion and de-adhesion. Current work is directed toward identifying pharmacological strategies to block the pro-metastatic functions of CDCP1. (Law, M., et al. Oncogene (2013) 32:1316; Law, M., et al. Breast Cancer Research (2016) 18:80)

Activation of Death Receptors 4 and 5 by Altered Disulfide Bonding as a New Approach to Cancer Therapy: Our collaborative team identified a novel class of anticancer agents termed Disulfide bond Disrupting Agents (DDAs). DDAs selectively kill cancer cells that overproduce the oncoproteins Epidermal Growth Factor Receptor (EGFR/HER1), the EGFR family member, HER2, or the transcription factor MYC. DDA-induced cell death is mediated by the Death Receptors DR4 and DR5, which activate the Caspase 8-Caspase 3 pro-apoptotic cascade. Current work focuses on elucidating the molecular mechanisms by which DDAs activate DR4/5. (Wang, M., et al. Cell Death Discovery (2019) 5:153; Wang, M., et al., Oncogene (2019) 38:4264)   Identification of the First Active Site Inhibitors of the Disulfide Isomerases ERp44 and AGR2 as Novel Anticancer Agents: Affinity-tagged DDA molecules were used to identify the Protein Disulfide Isomerases ERp44, AGR2/3, and PDIA1 as the direct DDA target proteins in cancer cells that mediate DDA actions. Ongoing efforts are focused on understanding the structural features of the DDAs and their target proteins that control DDA target selectivity, and on determining the role of the DDA target enzymes in regulating the disulfide bonding patterns of their client proteins, Death Receptors 4 and 5, and the HER-family receptor tyrosine kinases EGFR and HER2. (Law, M., et al. bioRxiv preprint doi: https://doi.org/10.1101/2021.01.13.426390)

Prescription opioid overdose is increasing at a rapid rate. Respiratory depression is the primary cause of death from opioid overdose, yet surprisingly, very little is known about the mechanisms of opioid-induced respiratory depression. Breathing, like other motor behaviors, is coordinated by a central neural network. The goal of the Levitt Lab is to understand how opioids modulate neurons in the respiratory network to cause breathing disturbances. A variety of cellular and systems level approaches — including brain slice electrophysiology, single unit and whole nerve recordings from a unique preparation with an intact respiratory network and in vivo-like respiratory cycle, and plethysmography in awake animals — are used to achieve this goal.

The Martens Lab is focused in two areas of Pharmacology and Therapeutics, including sensory Neuropharmacology and cardiovascular Pharmacology, with work in both the heart and olfactory systems.

In relation to the olfactory system, the lab’s work is devoted to understanding mechanisms of olfaction, pathogenesis of olfactory dysfunction, and the development of curative therapies for anosmia. Olfactory dysfunction in the general population is frequent, affecting at least 2.5 million people in the U.S. alone. In at least 20% of the cases, the etiology of the chemosensory disturbance cannot be identified. The Martens Lab was one of the first to demonstrate olfactory dysfunction as a clinical manifestation of an emerging class of human genetic disorders, termed ciliopathies, which involve defects in ciliary assembly, maintenance, and/or function. Most importantly, the lab has demonstrated that gene therapy can be used to successfully rescue anosmia resulting from the malformation/loss of cilia. Projects in the laboratory seek to identify direct mechanisms by which sensory input and deprivation regulate olfactory function and to learn how these are disrupted in disease states. Specifically, they work to elucidate the mechanisms underlying the transport of odorant signaling proteins into cilia of olfactory sensory neurons and their alterations in cilia-related disorders. In addition, work completed in the laboratory seeks to understand the importance of cilia for neurogenesis and cell differentiation, investigating their contribution to the regenerative properties of olfactory basal stem cells. Together, this work contributes to the understanding of the pathogenesis of human sensory perception diseases and paves the way for the development of treatments for olfactory loss in humans, where no curative therapies for ciliopathic disease exist.

In relation to the cardiovascular system, projects in the Martens Lab are focused on the identification of novel targets for the treatment of cardiac arrhythmias. In particular, the lab is interested in therapies for atrial fibrillation, which is the most common cardiac arrhythmia, affecting more than 2 million Americans. This electrical instability in the human heart can occur through a primary genetic defect in ion channel function or an acquired disorder attributable to ion channel dysregulation. They are interested in the regulation of voltage-gated potassium (Kv) channels that are vital for atrial repolarization in the human heart. Work in their laboratory is devoted to understanding the details of Kv channel regulation, trafficking, and pharmacological modulation and to learning how this is all integrated into the broader context of normal cardiomyocyte signaling and the pathogenesis of disease.

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The overarching goal of the Moehle Laboratory is to understand the cellular, molecular, and circuitry changes that underlie symptoms of neurological disorders. Using this deep understanding of changes to the brain in disease, we will be able to leverage these discoveries into novel therapeutic strategies for these diseases with large unmet clinical needs. Utilizing genetically, pharmacologically, and biochemically defined models of neurological disorders (such as dystonia, Parkinson’s Disease, and Dementias) we will perform cutting edge pharmacological, electrophysiological, behavioral, biochemical, and in vivo fiber photometry techniques to interrogate the cellular, molecular, and circuitry level changes in the central nervous system in these model systems. These studies have the possibility to make substantial advances in our understanding of brain wide changes in diseases such as Parkinson’s Disease, dystonia, and dementias as well as provide the pre-clinical rationale to direct larger drug discovery efforts for unique targets in these disorders.

Odors, pheromones, and taste stimuli contain important information about the quality and nutrient content of food, the suitability of mates, and the presence of predators or competitors. To detect these diverse chemical cues, animals employ several distinct populations of chemosensory cells in the nose, mouth and gut, each of which expresses specialized receptors, channels and transduction cascades, though the physiological consequences of this molecular diversity remain poorly understood. In the Munger Lab, they are working to understand how diverse chemosensory transduction mechanisms, including different taste and olfactory receptors, contribute to chemosensory function, impact ingestive and social behaviors, and interact with hormonal systems that regulate metabolism, nutrient response and homeostasis. Current areas of research include:

1) Mechanisms of alimentary chemosensation: They are investigating the interactions between taste and hormonal systems. A key function of the taste system is to detect nutrients, toxins, and indicators of spoilage, thus providing the animal with critical information about the quality and nutritional value of food before it is ingested. The ability to detect and discriminate taste stimuli is essential for health and survival, and it can drive ingestive behaviors. Therefore, physiological mechanisms that modulate taste function in the context of nutritional needs and metabolic status could optimize ingestive decisions and directly impact human health. Although the gustatory system critically influences food preference, food intake, and metabolic homeostasis, the physiological mechanisms that link taste function and metabolism are poorly understood. Recent findings from their laboratory and others suggest that the gustatory and gastrointestinal systems utilize a common molecular toolkit of receptors, signaling molecules, and hormones to detect nutrients and other chemicals. This is consistent with a role for taste function in the maintenance of metabolic homeostasis and suggests that sensory function may be modulated in the context of metabolic status.

2) Extraoral chemoreceptors and the regulation of metabolism: The T1R and T2R families of G protein-coupled receptors play critical roles in the taste system, where they mediate the detection of sweet, savory, and bitter-tasting stimuli. However, in recent years, it has become clear that these same receptors are expressed in numerous tissues throughout the body. Some of these extraoral “taste” receptors may facilitate metabolic responses to ingested nutrients, while others may protect the body from inhaled or ingested toxins. Currently, the Munger Lab is using in vivo and in vitro approaches to characterize the roles of these two receptor families in the detection of chemostimuli by endocrine cells of the gut, pancreas, and thyroid. These studies should offer important new insights into the molecular and cellular mechanisms underlying metabolic diseases such as obesity, Type 2 diabetes mellitus, the metabolic syndrome, and thyroid dysregulation.

3) Olfactory detection of social cues: It has become increasingly clear that the concept of a single olfactory system is grossly oversimplified. The olfactory system is actually composed of a number of subsystems, some well-known and others only recently characterized. These subsystems may be anatomically segregated within the nasal cavity, and they each make distinct neural connections to regions of the olfactory forebrain. They are clearly distinguished by the receptors they express and the signaling mechanisms they employ to detect and transduce chemosensory stimuli, and they respond to a plethora of diverse molecules, sometimes quite specifically, that range from volatile odors to peptides and proteins. The Munger Lab is using integrative approaches in mice to decipher the transduction mechanisms of these specialized subsystems, the ways in which the forebrain processes these signals, and the specific behaviors that they mediate. Of particular interest is the GC-D/necklace subsystem, which is specialized to detect chemosignals that facilitate food-related social learning. Ongoing efforts are geared to understanding whether this system can be harnessed to promote the ingestion of specific edibles in the context of pest control and animal feeding.

The Papke Lab studies the physiology, pharmacology, and biophysics of neurotransmitter receptors with a special emphasis on the function of nicotinic acetylcholine receptors in the brain. These are the receptors that mediate the effects of nicotine on human behavior. The lab studies how these neuronal nicotinic acetylcholine receptors function as ligand-gated ion channels, identifying parts of the molecule that are involved with the binding of neurotransmitter and the conformational change associated with receptor activation. The lab is also characterizing the selectivity of experimental nicotinic agonists for specific receptor subtypes in the brain. With this understanding, they hope to identify the mechanisms through which nicotine-like substances may alleviate some of the learning and memory impairments in animal models of dementia. The ongoing clinical development of new experimental drugs may lead to novel therapeutics for the treatment of Alzheimer’s disease.

The Rowe Lab is interested in the cellular function of nuclear and organellar DNA topoisomerases and their role as targets for cancer and malarial chemotherapy. DNA topoisomerases are an ubiquitous class of enzymes that regulate the structure and function of cellular chromosomes. These enzymes are also targets of important anticancer (e.g., anthracyclines, epipodophyllotoxins, amsacrines, and camptothecins) and antimicrobial (fluoroquinolone) drugs. Most recently, the lab’s efforts have focused on the identification of a type II topoisomerase that is associated with the novel 35 kb circular plastid DNA of the malarial parasite P. falciparum. The 35 kb plastid DNA is thought to be localized within the apicoplast, a non-photosynthetic plastid an organelle of unknown function which has no counterpart in mammalian cells. Pharmacologic and genetic evidence indicate that the topoisomerase activity associated with the 35 kb plastid DNA is related to the bacterial type II topoisomerase DNA gyrase. The lab is currently investigating whether this novel topoisomerase might provide a selective target for the development of new antimalarial drugs. They are also interested in identifying the role of this unusual topoisomerase in the regulation of the novel 35 kb plastid genome of malaria.

There are two broad focuses of Dr. Sweeney’s current research program. The first grew out of his desire to understand the molecular basis of muscle contraction, and the molecular motor powering muscle contraction, myosin. He has been working in the area of myosin structure and function since the mid-1980s, and has authored a large number of papers on the subject, beginning in 1986. His lab was the first to publish the use of the baculovirus-SF9 expression system for the heterologous expression of myosin in the early 1990s. They published the first structural evidence for the lever arm hypothesis for myosin in 1995, and at the same time discovered the mechanism for ADP-release-associated load sensing in myosin. In the late 1990’s they hypothesized that myosin VI might be a reverse-direction myosin motor based on its primary sequence, which they were able to demonstrate experimentally. It was a paradigm-shifting discovery and remains the only know reverse-direction myosin. They also unraveled the kinetic basis for the processivity of myosin V, which applies to many classes of unconventional myosins. Recently, they described how actin activates the motor activity of all myosin classes. They are currently focused on the role of unconventional myosins in hearing, as well as evaluating the possibility that they may be drug targets in certain forms of cancer.

The second focus of his research is on muscle disease. This evolved from his desire to understand the processes involved in force generation and transmission by muscle, and diseases that result from defects in the proteins involved. This has included congenital forms of cardiomyopathy as well as muscular dystrophies. He has been working in the area of muscular dystrophy since 1992 and has authored a number of papers on evaluating potential therapeutic targets, beginning in the late 1990s. His lab has been working on the development of AAV gene transfer to liver, skeletal muscle, and to the heart in dogs, as well as small molecule therapies for inherited human diseases. He is the senior author on the paper describing their development of the nonsense suppression drug, PTC 124 (ataluren). His lab continues to work on the development of small molecules for the treatment of muscular dystrophies.

Dopamine (DA) is a catecholamine neurotransmitter found in the mammalian brain and regulates many critical physiological processes such as movement, cognition, motivation, reward/pleasure, and hormone regulation. Dysfunction of the dopamine system has been implicated in many brain disorders, including Parkinson’s disease (PD), schizophrenia, OCD, and ADHD. The goal of the Urs Lab is to study the role of genetic and environmental factors on dopamine neurotransmission and to learn more about the dopamine system by deciphering, a) signaling pathways involved in DA neurotransmission, b) functional dopamine neuronal circuits, and c) how these integrate and manifest behaviorally in an organism (mouse). Using these integrated approaches—in parallel—will allow us to fine-tune dopamine neurotransmission and devise novel drug- and gene-based therapeutic approaches to treat dopamine-related disorders such as PD and schizophrenia.

The Wesson Lab explores the neural processing of sensory information in the context of behavior. This line of questioning provides an ideal platform to test specific hypotheses regarding the neural basis of sensory dysfunction in neurological disorders, including dementias and addiction, wherein sensory processing is aberrant. To accomplish these major goals, they utilize a variety of methods, ranging from multi-site electrophysiological recordings or optical imaging from defined brain structures in behaving animals to cutting-edge operant behavioral assays, some of which they perform in viral/genetic animal models with precise neural perturbations. The goals for their research include:

1) Define brain systems for sensory information processing and motivated behaviors:

The ventral striatum (VS) is an integrative network of brain structures, which: 1) processes sensory information, and 2) is necessary for both motivated behaviors and the rewarding effects of psychostimulants. The olfactory tubercle (OT) subregion of the VS resides in a likely advantageous position for guiding motivated behaviors, since it both receives monosynaptic input from the olfactory bulb and also has direct interconnectedness with other VS regions and the basal ganglia. The role of the OT in sensory-driven motivated behaviors is not defined.

A major line of research in the Wesson Lab, therefore, is to identify manners whereby the OT encodes odor sensory information and to learn how this information consequently gets distributed throughout interconnected brain structures. They are also interested in defining sources of information into the OT. Work from their group is the first to demonstrate how neurons in the OT encode odor information in behaving subjects and how these processing strategies are shaped by the learned meaning of the odors (viz., valence). They are now working to identify complementary cellular mechanisms of odor valence and understand how this information is distributed among interconnected neural ensembles.

A related major line of research in the Wesson Lab is regarding the OT’s role in motivated behaviors. Despite elegant work showing that the OT is needed for both reward behavior and psychostimulant effects on behavior, the OT is not even incorporated into many prevalent models of the brain’s reward system. This omission may in part be explained by a lack of the specific cellular mechanisms whereby the OT impacts reward-guided behavior. Work from their group is the first to demonstrate how neurons in the OT encode goal-directed actions and natural reinforcers and how these are dictated by the motivational state of the animal. Ongoing work in this lab is now resolving important features whereby the OT subserves motivated behaviors. This work is highly relevant to understanding brain mechanisms of addictive behaviors.

2) Determine why, and how, the olfactory system is vulnerable to early onset dementias, including Alzheimer’s disease and Parkinson’s disease:

A question of wide importance to the understanding of AD and PD is how these diseases progress. At a circuit level, this problem can be thought of specifically by the following question: How can subtle and sometimes undetectable levels of local pathogens result in severe, wide-spread nervous system dysfunction? The lab addresses this question in the mammalian olfactory system, which yields ideal tractability for physiological recordings as well as a nearly linear, yet also distributed, information processing stream. This is a clinically-relevant model, especially given the early presence of some AD and PD neuropathology (during early Braak & Braak stages) in the olfactory bulbs of persons afflicted with the disease. The lab’s work seeks to allow the direct assessment of the cellular-level contributions of peripheral nervous dysfunction (‘upstream’) on central (‘downstream’) processing of behaviorally/perceptually-relevant information in the context of AD and PD and will therefore yield novel data on circuit progression of these diseases.

3) Define mechanisms whereby the olfactory system is shaped by cognitive state:

Cognition shapes sensory processing. Work by numerous groups has shown that olfactory perception and odor processing are both influenced by cognitive factors. The influence of attention, specifically, on the cellular processing of odors is entirely unknown. This is a very intriguing question, since olfactory cortical structures receive direct olfactory input in the absence of a thalamic relay—the proposed origin of attentionally-mediated effects in other sensory systems. Therefore, ongoing work in the Wesson Lab has invested into developing a sophistical behavioral tool to allow for manipulating selective attention to odors and testing important questions regarding the mechanisms, whereby attention shapes the representation of odor information in the brain. This work is relevant for understanding how information travels within the brain in the context of moment-to-moment changes in cognitive state, which can be impacted in many neurological disorders.