Molecular & Cellular
Carmela Abraham, Ph.D. (Professor, Member of the GPN GEC, Department of Biochemistry (BUMC)) studies the mechanisms of brain aging and the etiology of Alzheimer’s disease (AD). The 40-42 amino acid amyloid beta peptide (Aß) is the major component of plaques that accumulate in the brains of AD patients and are believed to cause irreversible mental deterioration. Formation and clearance of the neurotoxic Aß are major therapeutic targets for the treatment of AD. Aß is a proteolytic fragment of the amyloid precursor protein (APP), a ubiquitously expressed and conserved protein., The Abraham laboratory is conducting a screen to identify inhibitors of APP dimerization, because of its importance for Aß production, and has identified a proteolytic activity involved Aß degradation. Her laboratory also studies the aging rhesus monkey as a model for normal human brain aging because they develop cognitive impairment with age. To their surprise, they could not detect cortical neuronal loss, but extensive changes in the white matter and particularly in myelin. They attribute these changes that occur with aging to neuroinflammation, a major area of their research interests along with the anti-aging gene Klotho that is markedly reduced in oligodendrocytes.
J. Krzysztof Blusztajn, Ph.D. (Professor, Department of Pathology (BUMC)) studies the effects of perinatal availability of an essential nutrient, choline, on brain development and aging in experimental animals. This research endeavors to determine why it is that supplementation with choline during critical perinatal periods in rats and mice causes a long-term facilitation of visuospatial memory which persists until old age. To this end they are utilizing biochemical, neuroanatomical, and behavioral techniques in a highly unified experimental design. Their studies to date have focused on the development of the basal forebrain cholinergic system, hippocampal MAPK and CREB signaling, and on the developmental patterns of brain gene expression. They are also the first to show that choline nutrition in pregnancy alters the epigenome of the brain.
Jiang-Fan Chen, M.D., Ph.D. (Associate Professor, Departments of Neurology and Pharmacology (BUMC)). In the laboratory of molecular pharmacology, Dr. Chen’s research focuses on the neurobiology of adenosine and the A2A adenosine receptor and the role they may play in the development and treatment of neuropsychiatric disorders. Dr. Chen has developed an A2A receptor knockout mouse model and couples this genetic approach with pharmacological manipulation to explore the pathophysiological role of A2A receptors in animal and cellular models of neuropsychiatric disorders. The knowledge derived from these studies may provide the neurobiological basis for rational development of A2A receptor agents as treatment strategies for neuropsychological disorders, ranging from Parkinson’s disease to drug addiction.
William Eldred, Ph.D. (Professor, Member of the GPN GEC and former Director of Program in Neuroscience, Department of Biology (CRC)) The laboratory studies nitric oxide (NO) that has normal physiological functions in every retinal cell type, and every retinal cell type can potentially make NO. NO is also involved in many ocular pathologies including diabetic retinopathy and inhibiting NO is often beneficial. NO signaling is regulated by many factors, both in normal retinal function and pathology, making it desirable to target just the pathological pathways. Research of the laboratory focuses on how NO can be selectively targeted to decrease the neuronal and vascular pathology in diabetic retinopathy. They are testing the following two hypotheses. 1) Diabetes increases the retinal levels of adrenomedullin (ADM), which in turn activates neuronal nitric oxide synthase (nNOS) to increase retinal NO production to pathological levels. These studies provide the first demonstration of the ADM/nNOS/NO signaling pathways in retina and their modulation in the neuronal and vascular pathology in diabetic retinopathy. 2) Neuronal and vascular pathology in diabetic retinopathy share similar molecular pathways and are amenable to similar pharmacological interventions. Their results will clarify the role of specific NOS isoforms and ADM in diabetic retinopathy and how these pathways can be optimally targeted to treat the pathology. Upregulation of ADM is also found in proliferative vitreoretinopathy, uveitis, vitreoretinal disorders, primary open angle glaucoma, and retinitis pigmentosa. A clearer understanding of the ADM/NOS/NO signaling pathways and how they can be manipulated in retina may have broad implications for much ocular pathology.
David H. Farb, Ph.D. (Professor and Chair, Member of the Executive Committee of the BU Center for Neuroscience, Department of Pharmacology (BUMC)) focuses on the identification of pharmacological treatments for mental disorders of learning and memory. His research integrates existing electrophysiological, behavioral, pharmacological, and molecular genetic technologies in a novel systems-level platform for assessing the impact of cognitive enhancers upon fundamental hippocampal systems for pattern separation (encoding), and pattern completion (retrieval) that are believed to be essential for cognition in all mammals, including man. Deficits in aspects of episodic memory dependent on hippocampal function are evident in a variety of mental disorders that have a huge social impact, including schizophrenia, autism, Alzheimer’s Disease, and normal aging. Existing pharmacotherapies for many such conditions are limited and carry substantial risk of adverse effects. High-density electrophysiological recordings in awake behaving rats are being used to identify deficits in hippocampal function that underlie cognitive deficits exhibited by aged animals and animals reared in social isolation, the latter being a model for environmental stress during development. A multidisciplinary approach that includes the techniques of neurophysiology, molecular biology, patch-clamp electrophysiology, cell biology, and molecular neuroanatomy are combined to elucidate the mechanisms and modalities of cognitive enhancers and the discovery of therapeutic treatments for disorders or diseases of the nervous system.
Xue Han, Ph.D. (Assistant Professor, Departments of Biomedical Engineering, Pharmacology and Experimental Therapeutics (CRC/BUMC)) Brain disorders represent the biggest unmet medical need, with many disorders being untreatable, and most treatments presenting serious side effects. The Han laboratory is discovering design principles for novel neuromodulation therapies. They invent and apply a variety of genetic, molecular, pharmacological, optical, and electrical tools to correct neural circuits that go awry within the brain. As an example, they have pioneered several technologies for silencing specific cells in the brain using pulses of light. They have also recently participated in the first pre-clinical testing of a novel neurotechnology, optical neural modulation. Using these novel neurotechnologies and classical ones such as deep brain stimulation (DBS), they modulate the function of neural circuits to establish causal links between neural dynamics and behavioral phenomena (e.g., movement, attention, memory, and decision making). One of their current interests is the investigation of how neural synchrony arises within and across brain regions, and how synchronous activity contributes to normal cognition and pathology.
David Harris, M.D., Ph.D. (Professor and Chair, Department of Biochemistry (BUMC)) The Harris laboratory studies prion diseases, including Creutzfeldt-Jakob disease and kuru, that are fatal neurodegenerative disorders now of great medical importance because of the emergence of “mad cow disease” in Europe and the U.S., and its likely transmission to human beings. These diseases are also of enormous scientific interest because they involve an entirely novel mechanism of biological information transfer: they result from a change in the conformation of an endogenous membrane glycoprotein (PrPC) that converts it into a pathogenic isoform (PrPSc) that is infectious in the complete absence of nucleic acid. To address this field, the laboratory utilizes several experimental systems including yeast, cultured mammalian cells, and transgenic mice. They employ a wide range of techniques, including cell labeling, protein chemistry, light and electron microscopy, proteomics, DNA microarray analysis, mouse genetics, neuropathology, and animal bioassays.
Tarik Haydar, Ph.D. (Associate Professor, Department of Anatomy and Neurobiology (BUMC)) The Haydar Laboratory of Neural Development and Intellectual Disorders uses a molecular neuroscience approach to study mammalian brain development, specifically focusing on the neural stem cells and precursors in the neocortex and hippocampus. The lab also investigates the cellular and genetic mechanisms of developmental disorders including those underlying mental retardation in Down syndrome using state of the art techniques such as in utero electroporation, in vivo genetic fate mapping and cell ablation.
Susan E. Leeman, Ph.D. (Professor, Department of Pharmacology (BUMC)) Dr. Leeman’s work focuses on the two peptides, substance P (SP) and neurotensin, which were isolated and chemically defined in her laboratory and lead to her membership in the National Academy of Sciences. Projects that are currently underway include: 1. the role of glycosylation of the NK1 receptor on its signal transduction pathways, 2. the roles of SP in several models of inflammation in the gastrointestinal tract, including post-surgical cell adhesion formation, and the effect of non-peptide SP antagonists. 3. the role of LITAF, a newly described transcription factor participating in TNF alpha synthesis in macrophages obtained from inflamed colonic tissue.
Jen-Wei Lin, Ph.D. (Professor, Department of Biology (CRC)) focuses on Cellular and molecular mechanisms of neurotransmitter secretion Neurotransmitter secretion is a complicated process that involves ion channel gating and secretion steps. In addition, the mobilization and recycling of synaptic vesicles are needed to maintain the function of a synapse and to contribute to synaptic plasticity. Ultimately, an understanding of the secretory events means that one can establish a kinetic scheme for this multi-step process and identify molecules responsible for each step. Therefore, a combined electrophysiological and molecular approach is used in the Wei-Lin laboratory to investigate these questions.
Jennifer Luebke, Ph.D. (Associate Professor, Department of Anatomy and Neurobiology (BUMC))
employs whole-cell patch-clamp and intracellular filling techniques to examine the electrophysiological and morphological properties of neurons in in vitro slices of monkey and mouse neocortex. Research is focused on action potential firing patterns (and underlying ionic currents), glutamatergic and GABAergic synaptic response properties and detailed dendritic architecture. Data from single neurons are incorporated into computational models in collaboration with mathematicians at Mt. Sinai School of Medicine. In addition, collaborations are ongoing with investigators at BUSM who use molecular biological (single cell PCR and microarray) and electron microscopic (ultrastructural analysis) techniques to examine cells from which recordings are obtained. Overall goals include: 1) to examine the individual and network properties of cells in the prefrontal cortex; 2) to determine the effects of normal aging on these properties in the rhesus monkey, and; 3) to determine the effects of amyloid and tau on these properties in transgenic mouse models of Alzheimer’s disease.
Hengye Man, Ph.D. (Assistant Professor, Department of Biology, (CRC)) is interested in the mechanisms in the expression of synaptic plasticity. Since most of synaptic transmission is mediated by glutamatergic AMPA receptors, the study has been focused on regulation of AMPA receptor expression, turnover and synaptic localization as well as synaptogenesis.
Shelley J. Russek, Ph.D. (Professor and Director of GPN, Department of Pharmacology and Experimental Therapeutics (BUMC)) The research of Dr. Russek focuses on the role of BDNF in brain plasticity of neural networks and in multiple neurologic and neuropsychiatric disorders, such as anxiety, epilepsy, autism, depression and schizophrenia. It is clear that BDNF plays a crucial role in organizing the response of the genome to dynamic changes in the extracellular environment that enable brain plasticity and it has emerged as one of the most important signaling molecules of diverse intracellular programs that maintain a healthy balance of excitation and inhibition in the brain. How BDNF transcriptionally controls the pool of important proteins that are the substrate of this balance in vivo, increasing as well as decreasing the number and kind of key proteins and enzymes, is not understood and is a major question of the Russek laboratory. How BDNF controlled gene networks in individual neurons may impact the dynamics of a neural circuit, such as the brain reward pathway, is also a major question of her research that employs a variety of techniques in molecular, cellular, and systems neuroscience.
Benjamin Wolozin, M.D., Ph.D. (Professor of Pharmacology and Experimental Therapeutics (BUMC)) is interested in the pathophysiology of neurodegenerative diseases focusing on the biology of proteins that accumulate as aggregates or regulate aggregation. For Parkinson’s disease they study alpha-synuclein and LRRK2. For work on amyotrophic lateral sclerosis they study TDP-43. Alzheimer research focuses on beta-amyloid, cholesterol and SORL1. The approaches used include cell and molecular biology, signal transduction, neurotoxicity, apoptosis and neuroprotection. Models include C. elegans, cell lines, primary neuronal cultures and pathological human tissues.