Bradford B Lowell

Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

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Publications (174)2145.68 Total impact

  • Michael J Krashes · Bradford B Lowell · Alastair S Garfield
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    ABSTRACT: The melanocortin system provides a conceptual blueprint for the central control of energetic state. Defined by four principal molecular components-two antagonistically acting ligands and two cognate receptors-this phylogenetically conserved system serves as a prototype for hierarchical energy balance regulation. Over the last decade the application of conditional genetic techniques has facilitated the neuroanatomical dissection of the melanocortinergic network and identified the specific neural substrates and circuits that underscore the regulation of feeding behavior, energy expenditure, glucose homeostasis and autonomic outflow. In this regard, the melanocortin-4 receptor is a critical coordinator of mammalian energy homeostasis and body weight. Drawing on recent advances in neuroscience and genetic technologies, we consider the structure and function of the melanocortin-4 receptor circuitry and its role in energy homeostasis.
    No preview · Article · Jan 2016 · Nature Neuroscience
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    ABSTRACT: Agouti-related peptide (AgRP) neurons of the hypothalamus play a key role in regulating food intake and body weight, by releasing three different orexigenic molecules: AgRP; GABA; and neuropeptide Y. AgRP neurons express various G protein-coupled receptors (GPCRs) with different coupling properties, including G s -linked GPCRs. At present, the potential role of G s -coupled GPCRs in regulating the activity of AgRP neurons remains unknown. Here we show that the activation of G s -coupled receptors expressed by AgRP neurons leads to a robust and sustained increase in food intake. We also provide detailed mechanistic data linking the stimulation of this class of receptors to the observed feeding phenotype. Moreover, we show that this pathway is clearly distinct from other GPCR signalling cascades that are operative in AgRP neurons. Our data suggest that drugs able to inhibit this signalling pathway may become useful for the treatment of obesity.
    Preview · Article · Jan 2016 · Nature Communications
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    ABSTRACT: The basal forebrain (BF) is an essential component of the ascending arousal systems and may be a key site through which the orexin (also known as hypocretin) neurons drive arousal and promote the maintenance of normal wakefulness. All orexin neurons also make dynorphin, and nearly all brain regions innervated by the orexin neurons express kappa opiate receptors, the main receptor for dynorphin. This is remarkable because orexin excites target neurons including BF neurons, but dynorphin has inhibitory effects. We identified the sources of dynorphin input to the magnocellular preoptic nucleus and substantia innominata (MCPO/SI) in mice and determined the effects of dynorphin-A on MCPO/SI cholinergic neurons using patch-clamp recordings in brain slices. We found that the orexin neurons are the main source of dynorphin input to the MCPO/SI region, and dynorphin-A inhibits MCPO/SI cholinergic neurons through κ-opioid receptors by 1) activation of a G protein-coupled inwardly-rectifying potassium (GIRK) current, 2) inhibition of a voltage-gated Ca(2+) current, and 3) presynaptic depression of the glutamatergic input to these neurons. Both the responses to dynorphin-A and to orexin-A desensitize, but co-application of dynorphin-A and orexin-A produces a sustained response. In addition, the polarity of the response to the co-application depends on the membrane potential of BF neurons; at -40 mV the net effect of the co-application is inhibition by dynorphin-A, whereas at -70 mV the excitatory response to orexin-A prevails. This suggests that depending on their state of activation, BF cholinergic neurons can be excited or inhibited by signals from the orexin neurons. This article is protected by copyright. All rights reserved.
    No preview · Article · Nov 2015 · The Journal of Physiology
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    ABSTRACT: The parabrachial nucleus is important for thermoregulation because it relays skin temperature information from the spinal cord to the hypothalamus. Prior work in rats localized thermosensory relay neurons to its lateral subdivision (LPB), but the genetic and neurochemical identity of these neurons remains unknown. To determine the identity of LPB thermosensory neurons, we exposed mice to a warm (36 °C) or cool (4 °C) ambient temperature. Each condition activated neurons in distinct LPB subregions that receive input from the spinal cord. Most Fos+ neurons in these LPB subregions expressed the transcription factor marker, FoxP2. Consistent with prior evidence that LPB thermosensory relay neurons are glutamatergic, all FoxP2+ neurons in these subregions co-localized with GFP in reporter mice for vglut2, but not for vgat. Prodynorphin (pdyn)-expressing neurons were identified using a GFP reporter mouse and formed a caudal subset of LPB FoxP2+ neurons, primarily in the dorsal lateral subnucleus (PBdL). Warm exposure activated many FoxP2+ neurons within PBdL. Half of the Fos+ neurons in PBdL were pdyn+, and most of these project to the preoptic area. Cool exposure activated a separate FoxP2+ cluster of neurons in the far-rostral LPB, which we named the rostral-to-external lateral subnucleus (PBreL). These findings improve our understanding of LPB organization and reveal that pdyn-cre mice provide genetic access to warm-activated, FoxP2+ glutamatergic neurons in PBdL, many of which project to the hypothalamus.
    No preview · Article · Oct 2015 · AJP Regulatory Integrative and Comparative Physiology
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    ABSTRACT: The nucleus accumbens (NAc) and the dynorphinergic system are widely implicated in motivated behaviors. Prior studies have shown that activation of the dynorphin-kappa opioid receptor (KOR) system leads to aversive, dysphoria-like behavior. However, the endogenous sources of dynorphin in these circuits remain unknown. We investigated whether dynorphinergic neuronal firing in the NAc is sufficient to induce aversive behaviors. We found that photostimulation of dynorphinergic cells in the ventral NAc shell elicits robust conditioned and real-time aversive behavior via KOR activation, and in contrast, photostimulation of dorsal NAc shell dynorphin cells induced a KOR-mediated place preference and was positively reinforcing. These results show previously unknown discrete subregions of dynorphin-containing cells in the NAc shell that selectively drive opposing behaviors. Understanding the discrete regional specificity by which NAc dynorphinerigic cells regulate preference and aversion provides insight into motivated behaviors that are dysregulated in stress, reward, and psychiatric disease. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Sep 2015 · Neuron
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    Full-text · Dataset · Jul 2015
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    ABSTRACT: Agouti-related-peptide (AgRP) neurons-interoceptive neurons in the arcuate nucleus of the hypothalamus (ARC)-are both necessary and sufficient for driving feeding behavior. To better understand the functional roles of AgRP neurons, we performed optetrode electrophysiological recordings from AgRP neurons in awake, behaving AgRP-IRES-Cre mice. In free-feeding mice, we observed a fivefold increase in AgRP neuron firing with mounting caloric deficit in afternoon vs morning recordings. In food-restricted mice, as food became available, AgRP neuron firing dropped, yet remained elevated as compared to firing in sated mice. The rapid drop in spiking activity of AgRP neurons at meal onset may reflect a termination of the drive to find food, while residual, persistent spiking may reflect a sustained drive to consume food. Moreover, nearby neurons inhibited by AgRP neuron photostimulation, likely including satiety-promoting pro-opiomelanocortin (POMC) neurons, demonstrated opposite changes in spiking. Finally, firing of ARC neurons was also rapidly modulated within seconds of individual licks for liquid food. These findings suggest novel roles for antagonistic AgRP and POMC neurons in the regulation of feeding behaviors across multiple timescales.
    Full-text · Article · Jul 2015 · eLife Sciences
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    ABSTRACT: Pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus (ARC) are oppositely regulated by caloric depletion and coordinately stimulate and inhibit homeostatic satiety, respectively. This bimodality is principally underscored by the antagonistic actions of these ligands at downstream melanocortin-4 receptors (MC4R) in the paraventricular nucleus of the hypothalamus (PVH). Although this population is critical to energy balance, the underlying neural circuitry remains unknown. Using mice expressing Cre recombinase in MC4R neurons, we demonstrate bidirectional control of feeding following real-time activation and inhibition of PVH(MC4R) neurons and further identify these cells as a functional exponent of ARC(AgRP) neuron-driven hunger. Moreover, we reveal this function to be mediated by a PVH(MC4R)→lateral parabrachial nucleus (LPBN) pathway. Activation of this circuit encodes positive valence, but only in calorically depleted mice. Thus, the satiating and appetitive nature of PVH(MC4R)→LPBN neurons supports the principles of drive reduction and highlights this circuit as a promising target for antiobesity drug development.
    No preview · Article · Apr 2015 · Nature Neuroscience
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    ABSTRACT: Summary paragraph Binge alcohol drinking is a tremendous public health problem because it leads to the development of numerous pathologies including alcohol abuse, and anxiety1–4. It is thought to do so by hijacking brain systems that regulate stress and reward, including neuropeptide Y (NPY) and corticotropin–releasing factor (CRF). The central actions of NPY and CRF play opposing functional roles in the regulation of emotional and reward–seeking behaviors; therefore, dysfunctional interactions between these peptidergic systems could play a role in the development of these pathologies. Here, we used converging physiological, pharmacological, and chemogenetic approaches to identify a precise neural mechanism in the bed nucleus of the stria terminalis (BNST), a limbic brain region involved in pathological reward and anxiety behaviors, underlying the interactions between NPY and CRF in the regulation of binge alcohol drinking in both mice and monkeys. We found that NPY Y1 receptor (Y1R) activation in the BNST suppressed binge alcohol drinking by enhancing inhibitory synaptic transmission specifically in CRF neurons via a novel, Gi-mediated, PKA-dependent postsynaptic mechanism. Further, chronic alcohol drinking led to persistent alterations in Y1R function in the BNST of both mice and monkeys, highlighting the enduring, conserved nature of this effect across mammalian species. Together, these data provide both a cellular locus and signaling framework for the development of novel therapeutics for treatment of neuropsychiatric diseases, including alcohol use disorders.
    No preview · Article · Mar 2015 · Nature Neuroscience
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    ABSTRACT: Leptin acts via its receptor (LepRb) on multiple subpopulations of LepRb neurons in the brain, each of which controls specific aspects of energy balance. Despite the importance of LepRb-containing neurons, the transcriptome and molecular identity of many LepRb subpopulations remain undefined due to the difficulty of studying the small fraction of total cells represented by LepRb neurons in heterogeneous brain regions. Here we sought to examine the transcriptome of LepRb neurons directly and identify markers for functionally relevant LepRb subsets. We isolated mRNA from mouse hypothalamic and brainstem LepRb cells by Translating Ribosome Affinity Purification (TRAP) and analyzed it by RNA-seq (TRAP-seq). TRAP mRNA from LepRb cells was enriched for markers of peptidergic neurons, while TRAP-depleted mRNA from non-LepRb cells was enriched for markers of glial and immune cells. Genes encoding secreted proteins that were enriched in hypothalamic and brainstem TRAP mRNA revealed subpopulations of LepRb neurons that contained neuropeptide-encoding genes (including prodynorphin, Pdyn) not previously used as functional markers for LepRb neurons. Furthermore, Pdyn (cre) -mediated ablation of Lepr (flox) in Pdyn-expressing neurons (LepRb (Pdyn) KO mice) blunted energy expenditure to promote obesity during high-fat feeding. TRAP-seq of CNS LepRb neurons defines the LepRb neuron transcriptome and reveals novel markers for previously unrecognized subpopulations of LepRb neurons.
    Full-text · Article · Feb 2015 · Molecular Metabolism
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    ABSTRACT: Hypoglycemia engenders an autonomically mediated counterregulatory (CR)-response that stimulates endogenous glucose production to maintain concentrations within an appropriate physiological range. Although the involvement of the brain in preserving normoglycemia has been established, the neurocircuitry underlying centrally mediated CR-responses remains unclear. Here we demonstrate that lateral parabrachial nucleus cholecystokinin (CCK(LPBN)) neurons are a population of glucose-sensing cells (glucose inhibited) with counterregulatory capacity. Furthermore, we reveal that steroidogenic-factor 1 (SF1)-expressing neurons of the ventromedial nucleus of the hypothalamus (SF1(VMH)) are the specific target of CCK(LPBN) glucoregulatory neurons. This discrete CCK(LPBN)→SF1(VMH) neurocircuit is both necessary and sufficient for the induction of CR-responses. Together, these data identify CCK(LPBN) neurons, and specifically CCK neuropeptide, as glucoregulatory and provide significant insight into the homeostatic mechanisms controlling CR-responses to hypoglycemia. Copyright © 2014 Elsevier Inc. All rights reserved.
    Preview · Article · Dec 2014 · Cell Metabolism
  • Clifford B Saper · Bradford B Lowell
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    ABSTRACT: The hypothalamus is one of the oldest and smallest parts of the brain, constituting just 4 gm of the 1400 gm of adult human brain weight. And yet this tiny area contains highly conserved neural circuitry that controls basic life functions: these include energy metabolism, from feeding through digestion, metabolic control, and energy expenditure; fluid and electrolyte balance, from drinking through fluid absorption and excretion; thermoregulation, from choice of environment through heat production and conservation, and fever responses; wake-sleep cycles and emergency responses to stressors in the environment; and reproduction, from reproductive hormone control through mating, pregnancy, birth, and suckling. In this Primer, we will give an overview of the structure of the hypothalamus, and outline what we know about how that relates to its functional circuitry. Copyright © 2014 Elsevier Ltd. All rights reserved.
    No preview · Article · Dec 2014 · Current Biology
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    ABSTRACT: Please check your proof carefully and mark all corrections at the appropriate place in the proof. Location in article Query / Remark: Click on the Q link to find the query's location in text Please insert your reply or correction at the corresponding line in the proof Q1 In the sentence, ''In contrast, no allodynia developed upon ablation of ChAT (Figure S6) or Npy (described elsewhere)..'' Do you want to provide a more specific citation? Thank you for your assistance.
    Full-text · Article · Nov 2014
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    ABSTRACT: Previous studies showed that Src homology-2 tyrosine phosphatase (Shp2) is an important regulator of body weight. In this study, we examined the impact of Shp2 deficiency specifically in proopiomelanocortin (Pomc) neurons on metabolic and cardiovascular function and on the chronic blood pressure (BP) and metabolic responses to leptin. Mice with Shp2 deleted in Pomc neurons (Shp2/Pomc-cre) and control mice (Shp2(flox/flox)) were implanted with telemetry probes and venous catheters for measurement of mean arterial pressure (MAP) and leptin infusion. After at least 5-days of stable control measurements, mice received leptin infusion (2 μg/kg/day, iv) for 7 days. Compared to Shp2(flox/flox) controls, Shp2/Pomc-cre mice at 22 weeks of age were slightly heavier (34±1 vs 31±1 g), but consumed a similar amount of food (3.9±0.3 vs 3.8±0.2 g/day). Leptin infusion reduced food intake in Shp2(flox/flox) mice (2.6±0.5 g) and Shp2/Pomc-cre mice (3.2±0.3 g). Despite decreasing food intake leptin infusion increased MAP in control mice, whereas no significant change in MAP was observed in Shp2/Pomc-cre mice. Leptin infusion also decreased plasma glucose and insulin levels in controls (12±1 to 6±1 μU/ml and 142±12 to 81±8 mg/100 ml) but not in Shp2/Pomc-cre mice. Leptin increased VO2 by 16 ± 2% in controls and 7 ± 1% in Shp2/Pomc-cre mice. These results indicate that Shp2 signaling in Pomc neurons contributes to the long-term BP and antidiabetic actions of leptin and may play a modest role in normal regulation of body weight.
    No preview · Article · Oct 2014 · AJP Regulatory Integrative and Comparative Physiology
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    ABSTRACT: Activation of melanocortin-4 receptors (MC4Rs) restrains feeding and prevents obesity; however, the identity, location, and axonal projections of the neurons bearing MC4Rs that control feeding remain unknown. Reexpression of MC4Rs on single-minded 1 (SIM1)(+) neurons in mice otherwise lacking MC4Rs is sufficient to abolish hyperphagia. Thus, MC4Rs on SIM1(+) neurons, possibly in the paraventricular hypothalamus (PVH) and/or amygdala, regulate food intake. It is unknown, however, whether they are also necessary, a distinction required for excluding redundant sites of action. Hence, the location and nature of obesity-preventing MC4R-expressing neurons are unknown. Here, by deleting and reexpressing MC4Rs from cre-expressing neurons, establishing both necessity and sufficiency, we demonstrate that the MC4R-expressing neurons regulating feeding are SIM1(+), located in the PVH, glutamatergic and not GABAergic, and do not express oxytocin, corticotropin-releasing hormone, vasopressin, or prodynorphin. Importantly, these excitatory MC4R-expressing PVH neurons are synaptically connected to neurons in the parabrachial nucleus, which relays visceral information to the forebrain. This suggests a basis for the feeding-regulating effects of MC4Rs.
    Preview · Article · Aug 2014 · Proceedings of the National Academy of Sciences
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    ABSTRACT: Whether melanocortin 4 receptors (MC4Rs) in extra-hypothalamic neurons, including cholinergic autonomic pre-ganglionic neurons, are required to control energy and glucose homeostasis is unclear. We found that MC4Rs in sympathetic, but not parasympathetic, pre-ganglionic neurons were required to regulate energy expenditure and body weight, including thermogenic responses to diet and cold exposure and 'beiging' of white adipose tissue. Deletion of Mc4r genes in both sympathetic and parasympathetic cholinergic neurons impaired glucose homeostasis.
    Full-text · Article · Jun 2014 · Nature Neuroscience
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    ABSTRACT: The adipocyte-derived hormone leptin plays a critical role in the central transmission of energy balance to modulate reproductive function. However, the neurocircuitry underlying this interaction remains elusive, in part due to incomplete knowledge of first-order leptin-responsive neurons. To address this gap, we explored the contribution of predominantly inhibitory (GABAergic) neurons versus excitatory (glutamatergic) neurons in the female mouse by selective ablation of the leptin receptor in each neuronal population: Vgat-Cre;Lepr(lox/lox) and Vglut2-Cre;Lepr(lox/lox) mice, respectively. Female Vgat-Cre;Lepr(lox/lox) but not Vglut2-Cre;Lepr(lox/lox) mice were obese. Vgat-Cre;Lepr(lox/lox) mice had delayed or absent vaginal opening, persistent diestrus, and atrophic reproductive tracts with absent corpora lutea. In contrast, Vglut2-Cre;Lepr(lox/lox) females exhibited reproductive maturation and function comparable to Lepr(lox/lox) control mice. Intracerebroventricular administration of kisspeptin-10 to Vgat-Cre;Lepr(lox/lox) female mice elicited robust gonadotropin responses, suggesting normal gonadotropin-releasing hormone neuronal and gonadotrope function. However, adult ovariectomized Vgat-Cre;Lepr(lox/lox) mice displayed significantly reduced levels of Kiss1 (but not Tac2) mRNA in the arcuate nucleus, and a reduced compensatory luteinizing hormone increase compared with control animals. Estradiol replacement after ovariectomy inhibited gonadotropin release to a similar extent in both groups. These animals also exhibited a compromised positive feedback response to sex steroids, as shown by significantly lower Kiss1 mRNA levels in the AVPV, compared with Lepr(lox/lox) mice. We conclude that leptin-responsive GABAergic neurons, but not glutamatergic neurons, act as metabolic sensors to regulate fertility, at least in part through modulatory effects on kisspeptin neurons.
    Preview · Article · Apr 2014 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: Pain information processing in the spinal cord has been postulated to rely on nociceptive transmission (T) neurons receiving inputs from nociceptors and Aβ mechanoreceptors, with Aβ inputs gated through feed-forward activation of spinal inhibitory neurons (INs). Here, we used intersectional genetic manipulations to identify these critical components of pain transduction. Marking and ablating six populations of spinal excitatory and inhibitory neurons, coupled with behavioral and electrophysiological analysis, showed that excitatory neurons expressing somatostatin (SOM) include T-type cells, whose ablation causes loss of mechanical pain. Inhibitory neurons marked by the expression of dynorphin (Dyn) represent INs, which are necessary to gate Aβ fibers from activating SOM+ neurons to evoke pain. Therefore, peripheral mechanical nociceptors and Aβ mechanoreceptors, together with spinal SOM+ excitatory and Dyn+ inhibitory neurons, form a microcircuit that transmits and gates mechanical pain.
    Full-text · Dataset · Apr 2014
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    ABSTRACT: Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to the control of hunger. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake. Consistent with their obligatory role in regulating appetite, genetic ablation or chemogenetic inhibition of AgRP neurons decreases feeding. Excitatory input to AgRP neurons is important in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric-state-dependent synaptic plasticity. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques in mice, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase-activating polypeptide (PACAP, also known as ADCYAP1). Chemogenetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric-deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.
    Full-text · Article · Feb 2014 · Nature
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    Alastair S Garfield · Bradford B Lowell
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    ABSTRACT: Aversive visceral stimuli, such as those associated with sickness, suppress appetite. Yet an understanding of the neural mechanisms underlying illness-related anorexia has remained elusive. Carter et al. (2013) now identify a specific hindbrain → amygdala circuit that contributes to illness-induced loss of appetite.
    Preview · Article · Dec 2013 · Cell metabolism

Publication Stats

30k Citations
2,145.68 Total Impact Points

Institutions

  • 1996-2015
    • Beth Israel Deaconess Medical Center
      • • Department of Medicine
      • • Department of Neurology
      • • Division of Endocrinology, Diabetes and Metabolism
      Boston, Massachusetts, United States
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2012
    • University of Texas Southwestern Medical Center
      • Division of Hypothalamic Research
      Dallas, Texas, United States
  • 1992-2012
    • Harvard Medical School
      • • Department of Medicine
      • • Department of Cell Biology
      Boston, Massachusetts, United States
  • 1990-2001
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 1998
    • University of Hamburg
      • Department of Internal Medicine II and Clinic (Oncology Center)
      Hamburg, Hamburg, Germany
  • 1997
    • National Institutes of Health
      • Branch of Surgery
      베서스다, Maryland, United States