Cell growth, differentiation and development; Cytoskeleton and cell motility; Genomics and proteomics; Molecular and Cellular Biology; Molecular Basis of Disease; Gene Expression; Signal Transduction; Cell Cycle
I am a cell biologist and bioengineer, and my primary research focuses on the rapidly growing area of cell mechanics and mechanotransduction: the role that mechanical forces play in regulating cellular function from healthy to diseased phenotypes. (1) Cardiovascular Biology, Mechanics and Disease: Funding source: American Heart Association (7/1/2018–6/30/2021; PI) Cardiovascular disease (CVD) is the main cause of death globally. Arterial stiffness is associated with many CVD. The molecular mechanisms governing arterial stiffening and the phenotypic changes in vascular smooth muscle cells (VSMCs) associated with the stiffening process are key areas in cardiovascular biology, mechanics and disease. Evidence suggests that arterial stiffening can drive aberrant migration and proliferation of VSMCs within the vessel wall. Yet, the underlying mechanisms regulating vascular stiffening and the molecular changes within VSMCs associated with the stiffening process remain unclear. While medications reduce hypertension, none specifically target pathways directly related to arterial stiffness. The overall goal of work in my lab is to address this gap in our understanding by investigating how changes in arterial stiffness affect VSMC function and fundamentally contribute to the progression of CVD. This study also addresses an important concept in vascular tissue remodeling (the interaction between extracellular matrix stiffness and VSMC behavior). Methodologically, my lab use a novel approach to dissect the molecular mechanism in VSMCs: My lab combines methods for manipulating and measuring tissue and cell stiffness using atomic force microscopy and traction force microscopy for simultaneously modulating substrate stiffness and measuring contraction force by culturing cells on a compliant substrate that mimics in vivo mechanical environments of the VSMCs. (2) Smooth Muscle Cell (and Cancer Cell) Heterogeneity: Highly heterogeneous responses of VSMCs to arterial stiffness or CVD make it difficult to dissect underlying molecular mechanisms. To overcome this, my lab integrates Mechanobiology, Vascular Cell Biology, and Machine Learning to manipulate stiffness and assess responses with unique precision. Machine learning is used to deconvolve inter- and intra-cellular heterogeneity and identify specific subcellular traits that correlate with stiffness and VSMC behavior. My lab also applies Machine Learning approaches to identify specific breast cancer cell behaviors that respond to different stiffness conditions. (3) Optogenetics and Biophotonics in Stem Cell Biology: Funding source: National Science Foundation (8/1/2017–7/31/2020; co-PI) Major breakthroughs in the field of genomics, embryonic stem cell biology, optogenetics and biophotonics are enabling the control and monitoring of biological processes through light. Additional research in my laboratory focuses on developing a nanophotonic platform able to activate/inactivate gene expression and, thus, control stem cell differentiation in neuronal cells, by means of light-controlled protein-protein interactions. More specifically, the light-controlled molecular toggle-switch based on Plant Phytochrome B and transcription factor Pif6 will be utilized to control the nuclear fibroblast growth factor receptor-1, which is a master regulator of stem cell differentiation. Open Positions: The Bae lab is currently accepting graduate students through the Pathology Masters program (or other programs) as well as motivated undergraduates. For Graduate Students: I am looking for one or two graduate (MS) students who understand my research interests, have read my previous publications, and have their own (crazy!!!) ideas as to where my research efforts should be directed. All graduate students are required to complete and submit internationally recognized Journal article(s) before graduation from my lab. A Masters thesis should generate at least one first author publication. For Undergraduate Students: I encourage all UB undergraduates (with GPA 3.0 or higher) to get "hands on" experimental training in the sciences. An undergraduate research project tends to be part of a larger whole, but I make sure to include credit for students work in presentations and publications.
Addictions; Drug abuse; Behavioral pharmacology; Cytoskeleton and cell motility; Gene Expression; Gene therapy; Neurobiology; Neuropharmacology; Signal Transduction; Transcription and Translation
Drug addiction is a disabling psychiatric disease leading to enormous burdens for those afflicted, their friends and family, as well as society as a whole. Indeed, the addict will seek out and use illicit substances even in the face of severe negative financial, family and health consequences. It is believed that drugs of abuse ultimately “hijack” the reward circuitry of the CNS leading to cellular adaptations that facilitate the transition to the “addicted” state As is the case with both rodent models of drug taking, and well as throughout the global human population, not all individuals exposed to drugs of abuse will meet the classical definition of being truly “addicted”. We are looking at how molecular and behavioral plasticity mediates susceptibility to drug abuse and relapse like behaviors.
Neurology; Cytoskeleton and cell motility; Molecular and Cellular Biology; Molecular Basis of Disease; Molecular genetics; Neurobiology; Signal Transduction; Inherited Metabolic Disorders; Transgenic organisms
My laboratory seeks to understand the molecular basis of myelination and myelin diseases. Myelin is a multi-lamellar sheath that invests large axons and permits rapid conduction of nerve signals. Failure in myelin synthesis and myelin breakdown cause several important neurological diseases, including multiple sclerosis, leukodystrophies and peripheral dysmyelinating neuropathies. In some of these diseases, genetic mutations cause defects in cytoskeletal, adhesion and signaling molecules. I work with a team of undergraduate and graduate students, postdoctoral fellows, technicians, senior scientists and many international collaborators to discover how these molecules normally coordinate cell-cell and cell-extracellular matrix interactions to generate the cytoarchitecture of myelinated axons. We use a variety of approaches, including generation of mice carrying genetic abnormalities, cultures of myelinating glia and neurons, imaging, biochemistry and morphology to understand the role of these molecules in normal and pathological development. By comparing normal myelination to the abnormalities occurring in human diseases, we aim to identify molecular mechanisms that pharmacological intervention might correct. For example, we described how the protein dystroglycan associates with different proteins, some of which impact human neuropathies, depending on a proteolitic cleavage that can be regulated to improve the disease. Similarly, we found that molecules such as integrins and RhoGTPAses are required for glia to extend large processes that will become myelin around axons. In certain neuromuscular disorders, defective signaling pathways that converge on these molecules cause failure to produce or mantain an healthy myelin Finally, in collaborations with scientists and clinicians in the Hunter J. Kelly Research Institute, we are generating transgenic forms of GalC, an enzyme deficient in Krabbe leukodystrophy, to investigate which cells requires the enzyme. Investigating how GalC is handled may help find a cure for this devastating disease.
Neurology; Neurodegenerative disorders; Pathophysiology; Apoptosis and cell death; Cytoskeleton and cell motility; Molecular and Cellular Biology; Molecular genetics; Neurobiology; Protein Folding; Gene Expression; Transcription and Translation; Signal Transduction; Toxicology and Xenobiotics
My research is aimed at finding the cause and a cure for Parkinson’s disease. Parkinson’s disease (PD) is defined by a characteristic set of locomotor symptoms (rest tremor, rigidity, bradykinesia and postural instability) that are believed to be caused by the selective loss of dopaminergic (DA) neurons in substantia nigra. The persistent difficulties in using animals to model this human disease suggest that human nigral dopaminergic neurons have certain vulnerabilities that are unique to our species. One of our unique features is the large size of the human brain (1350 grams on average) relative to the body. A single nigral dopaminergic neuron in a rat brain (2 grams) has a massive axon arbor with a total length of 45 centimeters. Assuming that all mammalian species share a similar brain wiring plan, we can estimate (using the cube root of brain weight) that a single human nigral dopaminergic neuron may have an axon with gigantic arborization that totals 4 meters. Another unique feature of our species is our strictly bipedal movement, which is affected by Parkinson’s disease, in contrast to the quadrupedal movement of almost all other mammalian species. The much more unstable bipedal movement may require more dopamine, which supports the neural computation necessary for movement. The landmark discovery of human induced pluripotent stem cells (iPSC) made it possible to generate patient-specific human midbrain dopaminergic neurons to study Parkinson’s disease. A key problem for dopaminergic neurons is the duality of dopamine as a signal required for neural computation and a toxin as its oxidation produces free radicals. Our study using iPSC-derived midbrain dopaminergic neurons from PD patients with parkin mutations and normal subjects shows that parkin sustains this necessary duality by maintaining the precision of the signal while suppressing the toxicity. Mutations of parkin cause increased spontaneous release of dopamine and reduced dopamine uptake, thereby disrupting the precision of dopaminergic transmission. On the other hand, transcription of monoamine oxidase is greatly increased when parkin is mutated. This markedly increases dopamine oxidation and oxidative stress. These phenomena have not been seen in parkin knockout mice, suggesting the usefulness of parkin-deficient iPSC-derived midbrain DA neurons as a cellular model for Parkinson’s disease. Currently, we are using iPS cells and induced DA neurons to expand our studies on parkin to idiopathic Parkinson’s disease. We are also utilizing the molecular targets identified in our studies to find small-molecule compounds that can mimic the beneficial functions of parkin. The availability of human midbrain DA neurons should significantly speed up the discovery of a cure for Parkinson’s disease.
Pathophysiology; Cytoskeleton and cell motility; Endocrinology; Eukaryotic Pathogenesis; Gene Expression; Molecular Basis of Disease; Molecular and Cellular Biology; Molecular genetics; Protein Function and Structure; Regulation of metabolism; Transcription and Translation
In my laboratory, we are interested in structural components of the cell, their role in establishing and regulating cellular functions, and how this regulation translates into physiological consequences in health and disease. We have two major focus areas: 1) The role of cytoskeletal elements in prostate cancer development and progression and 2) The role of nucleoskeletal elements in establishing and maintaining nuclear structure and function. 1) The majority of death from cancer is caused by metastasis, the spreading of cancer cells from the site of a primary tumor to other body parts. We use a combination of biochemical, cell biological, physiological, and translational approaches to elucidate the mechanisms that are involved in the acquisition of metastatic phenotypes. Specifically, we focus on the role that myosins play in this process. We are also interested in how dietary fats can contribute to the development of metastatic phenotypes in prostate cancer cells. 2) Aberrations in nuclear structure and dynamics are the underlying cause of diseases ranging from cancer to premature aging. We are interested in the role of nuclear actin and myosins in regulating dynamic nuclear processes such as nucleolar assembly and functions in health and disease.
Cardiovascular Disease; Cytoskeleton and cell motility; Molecular Basis of Disease; Molecular and Cellular Biology
My primary research interest is the behavior of endothelial cells, which form the inner lining of blood vessels and are key players in the remodeling events that occur during wound healing, aneurysm formation, tumor growth, and a wide variety of disease conditions. There are two questions about endothelial behavior that drive most of the research in my laboratory: (1) How does an endothelial cell migrate during wound healing and blood-vessel remodeling? We are particularly interested in the motor protein, myosin II, and how it exerts force within the cytoskeleton to push or pull the cell as it moves. In order to study the organization and movements of cytoskeletal proteins - and not just there biochemical properties - we use a variety of light microscopic methods to examine the dynamics and biochemistry of cytoskeletal proteins in living migrating endothelial cells. We also use conventional biochemical, genetic, and pharmacological manipulations to investigate the regulatory events that control myosin II behavior in situ. (2) How do endothelial cells sense and respond to their mechanical environment? Blood vessels remodel to accommodate long-term changes in blood flow. Certain flow environments can cause destructive remodeling that leads to cerebral aneurysms (local “ballooning” of vessels). Working with biomedical engineers in the laboratory of Dr. Hui Meng at the Toshiba Stroke Research Center, we use cell culture and whole animal systems to examine how endothelial cells respond to specific hemodynamic micro-environments in order to understand the mechanism and regulation of flow-induced remodeling, especially as it relates to cerebral aneurysms. A third interest is understanding the response of cultured endothelial cells to electrical fields, which have been shown to orient endothelial migration in vitro and to suppress edema in vivo by enhancing the endothelial permeability barrier.
Apoptosis and cell death; Cell growth, differentiation and development; Cytoskeleton and cell motility; Immunology; Signal Transduction; Stem Cells
My independent research at The University at Buffalo focuses on targeting the mammary gland microenvironment by evaluating cellular and tissue responses during specific developmental windows of mammary gland remodeling including puberty, the period of hormonal withdrawal during estrous cycling, or post-lactational involution. My choice to focus on discrete times of development for chemopreventive intervention, rather than long-term (and often life-time) intervention, represents a unique approach of short-term exposure at critical points of mammary gland development. Our goal is to allow women to bypass the need for lifelong compliance to a chemopreventive diet or drug regimen in order to attain lifelong protection against breast cancer. Developmentally targeted dietary interventions being investigated in our lab include continuous administration of oral contraceptives, dietary exposure to conjugated linoleic acid, and ethanol.
Cardiopulmonary physiology; Cytoskeleton and cell motility; Ion channel kinetics and structure; Membrane Transport (Ion Transport); Molecular and Cellular Biology; Molecular Basis of Disease; Signal Transduction
My research interests center on mechanical and electrical biophysics, from molecules to organs, and the development of new tools. And, in recent years I worked in transitional science; bringing basic science to the clinic and to industry. My basic research interests are on cell mechanics and the mechanisms by which mechanical forces are transduced into messages such as voltage and chemicals such as ATP and Ca2+. I discovered mechanosensitive ion channels in 1983. My methodology has included patch clamp, high resolution bright field light microscopy, low light fluorescence microscopy, high speed digital imaging, TIRF, digital image analysis, high voltage EM with tomography, Atomic Force Microscopy, molecular biology, natural product and recombinant protein biochemistry, NMR and microfabrication and microfluidics. We discovered the only known specific inhibitor of mechanosensitive ion channels and uncovered its remarkable mode action by using a combination of electrophysiology and chiral chemistry. We have demonstrated potential clinical applications of the peptide for cardiac arrhythmias, oncology, muscular dystrophy, and incontinence. We have developed many scientific tools. Recently we developed a sensor chip to measure cell volume in real time, and that is now entering production with Reichert Instruments of Buffalo. We also have an Small Business Innovation Research contract to develop a microfluidic, bipolar, temperature jump chip with ALA Scientific and developed a microfabricated Atomic Force Microscopy probe that is an order of magnitude faster and more stable than any commercial probes. We have made probe operable with two independent degrees of freedom on a standard Atomic Force Microscopy. This permits us to remove all drift and coherent noise by using one axis to measure the substrate position and the other the sample position. These probes are being produced by a new company in Buffalo, kBtwist. We have used the Atomic Force Microscope combined with electrophysiology to study the dynamics of single voltage dependent ion channels. This technique provides a resolution of >0.01nm in a kHz bandwidth. I have developed other hardware including the first automated microelectrode puller, a micron sized thermometer and heater and a high speed pressure servo. Some of these devices have been patented by the University of Buffalo and some are in current production. To analyze the reaction kinetics of single molecules, we developed and made publicly available (www.qub.buffalo.edu) a complete software package for Windows that does data acquisition and Markov likelihood analysis. The development was funded by the National Science Foundation, National Institutes of Health and Keck over the last fifteen years, and has been applied to ion channels, molecular motors and the even the sleep patterns of mice. We have taught at UB hands-on course to use the software, and the course was attended by an international group of academic scientists and students, government and industry.
Cell growth, differentiation and development; Cytoskeleton and cell motility; Stem Cells
Development of regenerative therapeutics involves understanding and application of molecular, cellular and tissue engineering principles. Integrated strategies include biomaterials, therapeutic molecules and stem cells to create bioengineered systems for regenerative medicine. Therefore, understanding fundamental interactions between different components and utilizing these concepts will provide tools to engineer tissue regeneration and develop treatment options for diseases. The translational aspect of regenerative medicine depends on proper integration of engineering and medicine. This hierarchical roadmap is tissue or disease specific and thus requires step-wise approaches. Our current goals are to develop strategies for therapeutic angiogenesis, soft and elastic tissue regeneration and delivery of drugs. We are interested to integrate the different components for effective therapeutic strategies
Neurodegenerative disorders; Pathophysiology; Cytoskeleton and cell motility; Molecular Basis of Disease; Molecular and Cellular Biology; Neurobiology; Neuropharmacology; Signal Transduction
Synaptic Mechanisms of Mental Health and Disorders Our research goal is to understand the synaptic action of various neuromodulators that are linked to mental health and illness, including dopamine, stress hormones, and disease susceptibility genes. Specifically, we try to understand how these neuromodulators regulate glutamatergic and GABAergic transmission in prefrontal cortex (PFC), which is important for emotional and cognitive control under normal conditions. We also try to understand how the aberrant action of neuromodulators under pathological conditions leads to dysregulation of synaptic transmission in PFC, which is commonly implicated in brain disorders. The major techniques used in our studies include: • whole-cell patch-clamp recordings of synaptic currents, • viral-based in vivo gene transfer, • biochemical and immunocytochemical detection of synaptic proteins, • molecular analysis of genetic and epigenetic alterations, • chemogenetic manipulation of neuronal circuits, • behavioral assays. By integrating the multidisciplinary approaches, we have been investigating the unique and convergent actions of neuromodulators on postsynaptic glutamate and GABAA receptors, and their contributions to the pathogenesis of a variety of mental disorders, including ADHD, autism, schizophrenia, depression, PTSD and Alzheimer‘s disease.