Department of Psychology; Neuroscience And Behavio
Fiocruz-Minas Caroline Junqueira, PhD - Staff Scientist Camila Brabosa, PhD student - Mapping of CD8 T cell-specifc Epitopes from Malaria Blood Stage Gregorio Almeida, DVM, PhD - Immunology of Asymptomatic Malaria Guilherme Maia, PhD - Innate Lymphocytes in Malaria Isabella Hirako, PhD - Monocyte-Derived Dendritic Cells in Malaria Júlia Castro, MSc student - Chagas Disease Vaccine Larissa Pereira, MSc student - Inflammatory Caspases in Malaria Kely Mateucci, PhD - Monocyte-Derived Dendritic Cells Metabolism in Malaria Milton Pereira, PhD - Caspases and inflammasomes in Malaria and Chagas Disease Natalia Satchiko Souza, PhD - CD8+ T cells in malaria UMASS Danielle Durso, PhD - IRAKs and Myddosomes in host resistance to T. gondii Patricia Assis, PhD - Host Clock genes and Malaria Ogooluwa Ojelabi, PhD - Glucose Metabolism and Malaria
Additional information about lab rotations within the CPHR program can be found athttp://www.umassmed.edu/cphr/program/rotations.aspx
Elisabeth Chair for the Dean of Medicine
Penelope Booth Rockwell Chair in Biomedical Research
Focus: Adeno-associated virus vector mediated gene transfer for gene therapy, gene therapy of inherited neurodegenerative Canavan Disease
Robert M. and Shirley S. Siff Chair in Autism
Dr. Esteves is a neuroscientist with interest in gene therapy to help treat neurodegenerative diseases.
Rotation Projects for graduate students: Examining the role of cross-reactive CD8 memory T cells in mediating the EBV-induced infectious mononucleosis syndrome in humans. Examining the role of cross-reactive CD8 memory T cells and cytokines in murine models of viral infection. Examining the mechanisms used by these memory T cells to unrelated infections to modulate disease outcome either for the bad or the good.
An entry level postdoctoral position is open immediately in the laboratory of Dr. Susan L. Swain to study the factors that control the development and survival of CD4 and CD8 T cell memory. Graduate student experience with tissue culture, in vitro assay, flow cytometry, experience in mouse models on infectious disease and a knowledge of cellular and molecular immunology are all strongly desired.
<p >Rotations: Projects in the following areas <p >CD4 T cell memory. We can generate in vitro CD4 T cells that are for all extents and purposes identical to the memory CD4 T cells observed in vivo. In situ memory CD4 T cells persist at very low frequency and in most instances it is difficult to analyze them thoroughly using tetramer or multimer reagents both because of their low frequency and the relatively low specific affinity of the Class II reagents for the TcR. Being able to generate “recent” memory cells in vitro gives us the opportunity to analyze in detail the mechanisms by which memory CD4 T cells may contribute to secondary immunity and immune protection. Once identified. will determine if particular pathways are relevant in situ. We have discovered that memory CD4 T cells are superior in protection to those from the primary response and that they display pleitropic functions that have not been previously identified. <p > Cytotoxic CD4 Effectors. One unexpected function of CD4 T cells we identified is robust, perforin-dependent cytotoxic activity (7, 16). Cytotoxic activity by CD4 T cells has been reported in response to several infections, but its significance has not heretofore been established. We find that “Th1 polarized” CD4 effectors and more relevantly the CD4 effectors found in the lung following influenza infection, are able to kill infected or peptide-pulsed Class II-bearing targets and we find that this perforin dependent activity can work together with antibody to provide protection against lethal influenza challenge in otherwise unprimed mice (17). We also will determine when memory CD4 T cells re-express cytotoxic activity following in vivo challenge and how cytotoxic killing contributes to the memory cell mediated protection. We want to analyze how the program of cytotoxicity is induced in these “ThCTL”. <p > Memory CD4 Cells Enhance an Innate Response. Memory cells can act by becoming secondary effectors but they are best characterized by their ability respond rapidly even to low antigen doses, by producing cytokines and chemokines and it is assumed that these initial abilities are key to memory cell activity. However this assumption has not been directly demonstrated and the mechanisms involved and how they might contribute to immunity have not been elucidated. We find that restimulation of memory CD4 T cells leads to a markedly enhanced early innate response to influenza infection both in the lung and systemically (17). This response peaks 2-3 days after infection and is transient. We see enhanced production of IL-6 locally and systemically and enhanced production a broad spectrum of innate inflammatory mediators in the lung. We hope to determine in detail the pathways leading to optimum memory T cell-induced innate responses. We suggest a concurrent activation of CD4 memory cells may be an effective adjuvant for vaccination and will be testing this hypothesis as well as mechanisms that lead to viral control over the next couple of years. <p >Aging and Immunity: The study of the impact of aging on CD4 T cell function at the naïve and memory stages has lead us to better understanding of fundamental aspects of T cell behavior in addition to providing important information about what vaccine approaches are most likely to be successful for the aged. Nature of CD4 Aging “Defects”. We have identified multiple levels at which aged naïve CD4 T cells are defective including initial early response to TcR triggering, IL-2 production, expansion and effector generation. The defects in helper function and in the 20 response of memory cells generated from aged naïve CD4 T cells are particularly dramatic. In recent studies we have recapitulated memory age-associated defects in recently generated memory cells in vitro (23). In vitro aged memory cells are markedly defective in production of particular cytokines, IL-4, IL-5 and IL-2, while others are little affected (IFNg, IL-10, TNF), suggesting the aging “defect” may be restricted to loss of potential to make certain CD4 T cell subsets, such as those responsible for help to B cells .We will pursue this hypothesis both in vitro and in vivo. <p >We have found that aged naïve CD4 T cells are in fact longer-lived than their naïve counterparts (23). We find that reduced expression of Bim, a proapoptotic protein, is responsible for this increase in lifespan and that the increase in lifespan is required for the development of aging defects. We are now investigating the factors that regulate Bim expression. <p >Enhancement by Inflammatory Cytokines. We have shown that the defective effector generation responses of naïve CD4 T cells from aged animals can be overcome by IL-2 and by proinflammatory cytokines, in particular a mix of IL-1, IL-6 and TNF (20,21). We want to determine the extent to which the inflammatory cytokines can reverse the heritable aging defects and restore functional memory generation. We have developed in vitro models to test the generation of effectors and memory. In these models we are evaluating TLR agonists for their ability to restore aged naïve CD4 responses to peptide-pulsed derived dendritic cells (DC). Pre-incubation of DC with many TLR agonists, enhances expansion of the responding aged naïve CD4 T cells via a mechanism dependent on IL-6 that acts in part by increasing survival of the developing effector population. We plan to use this model to identify the extent of the rescue and what pathways and mechanisms contribute with the ultimate goal of evaluating whether specific TLR stimulation or stimulation of specific pathways might improve the response of the elderly to vaccines. We want to see if we can reproduce this model with human naïve CD4 T cells and DC derived from peripheral blood and if TLR agonists can also enhance those responses. <p >
David J. Freelander Memorial Professor in AIDS Research
Worcester Foundation for Biomedical Research Chair III
Please email Kate.Fitzgerald@umassmed.edu if you are interested in rotations.
Dr. Henninger is a vascular neurologist with research interest in the neurobiology of axonal injury associated with traumatic brain injury and its contribution to functional outcome.
Immediate opening! Two postdoctoral positions are available immediately to study cellular andmolecular mechanisms resulting in immunosuppression after alcohol use. Thefocus of this research is the role of monocytes and dendritic cells indecreased antigen-specific T cell activation after alcohol use.Intracellular signalling mechanisms resulting in decreased NF-kBactivation and inflammatory cytokine induction after acute alcoholconsumption are being investigated. Please contact Dr. Szabo for details.
Background for Student Rotation Projects <p >See Politz, Hogan and Pederson (2009) and Politz et al. (2005) in the above list. The novel microRNA work may be the most suitable for student rotations. Potential Rotation Projects <p >Are the nucleolar microRNAs pri-, pre- or mature? <p >Are they complexed with other nucleolar RNAs? <p >Do the cell cycle related proteins in the nucleolus exist as heterotypic complexes? <p >Does the nucleolus of human embryonic stem cells also share these features (which we have so far looked for, and found, only in transformed human cell lines)? <p >Can vanadium tagging be used to detect specific proteins by electron microscopy, perhaps exceeding the limitations of immuno-EM?
A postdoctoral position is available to study in this laboratory. Contact Dr. Rogaev for additional details.
Focus: Paramyxovirus and Pneumovirius membrane fusion and virus assembly, virus vaccines
Lambi and Sarah Adams Chair in Genetic Research
Rotations: Targeting the IFN-?-chemokine axis for treatment of vitiligo: We are using our newly developed mouse model and human tissues from patients with vitiligo to identify the cytokines and chemokines that are expressed within the depigmenting skin and which skin cells produce them. We are using genetically modified mouse strains (knockouts, conditional knockouts, fluorescent reporter strains), and cytokine and chemokine neutralizing antibodies to identify the key proteins required for disease. This data will permit us to rationally develop and test new therapeutic agents. Understanding the proinflammatory signals generated by melanocytes under cellular stress. Melanocytes from vitiligo patients have intrinsic abnormalities, including cellular stress evidenced by increased production of reactive oxygen species (ROS) and activation of the unfolded protein response (UPR). The immune system has evolved to recognize this stress as damage-associated molecular patterns (DAMPs), which activate innate immunity. We are using human cells and tissues to determine how cellular stress, innate immunity, and adaptive immunity cooperate to initiate and perpetuate depigmentation in vitiligo. Developing a humanized mouse model of immune-skin interactions to serve as a pre-clinical bridge to clinical studies: We are developing a humanized mouse model of skin disease that consists of an immunodeficient mouse strain as a host for an autologous human skin graft and immune reconstitution in order to study mechanisms of inflammation in the skin, including allergic contact dermatitis, response to infection, tumor immunotherapy, and autoimmunity, all within a fully human environment. This model system will act as a pre-clinical bridge between mouse models and human clinical trials, providing an opportunity to test new treatments on human cells and tissues prior to initiating trials on patients. Tracking real-time autoreactive T cell migration and interactions within the skin: We are using fluorescently/bioluminescently tagged CD8 T cells to track their movements and interactions within the skin in live mice, using real-time confocal microscopy and bioluminescent imaging. Initial studies will focus on the role of cytokines and chemokines in T cell migration within the skin. Clinical trial to test a novel treatment for vitiligo: We are in the early stages of developing a clinical trial based on insights developed from our animal data to test a novel drug for its ability to treat vitiligo.
Rotations: Targeting the IFN-g-chemokine axis for treatment of vitiligo: We are using our newly developed mouse model and human tissues from patients with vitiligo to identify the cytokines and chemokines that are expressed within the depigmenting skin and which skin cells produce them. We are using genetically modified mouse strains (knockouts, conditional knockouts, fluorescent reporter strains), and cytokine and chemokine neutralizing antibodies to identify the key proteins required for disease. This data will permit us to rationally develop and test new therapeutic agents. Understanding the proinflammatory signals generated by melanocytes under cellular stress. Melanocytes from vitiligo patients have intrinsic abnormalities, including cellular stress evidenced by increased production of reactive oxygen species (ROS) and activation of the unfolded protein response (UPR). The immune system has evolved to recognize this stress as damage-associated molecular patterns (DAMPs), which activate innate immunity. We are using human cells and tissues to determine how cellular stress, innate immunity, and adaptive immunity cooperate to initiate and perpetuate depigmentation in vitiligo. Developing a humanized mouse model of immune-skin interactions to serve as a pre-clinical bridge to clinical studies: We are developing a humanized mouse model of skin disease that consists of an immunodeficient mouse strain as a host for an autologous human skin graft and immune reconstitution in order to study mechanisms of inflammation in the skin, including allergic contact dermatitis, response to infection, tumor immunotherapy, and autoimmunity, all within a fully human environment. This model system will act as a pre-clinical bridge between mouse models and human clinical trials, providing an opportunity to test new treatments on human cells and tissues prior to initiating trials on patients. Tracking autoreactive T cell interactions within the skin: We are using fluorescently tagged CD8 T cells to track their cellular interactions within the skin using confocal microscopy. Future studies will adapt this model to investigate real-time migration and other movements of these cells within compartments of the skin. Clinical trial to test a novel treatment for vitiligo: We recently completed a clinical trial based on insights developed from our animal data to test a novel drug for its ability to treat vitiligo.
Interests: Vitiligo, autoimmunity, immunology, translational research
Arthur F. and Helen P. Koskinas Professor in Biochemistry and Molecular Biotechnology
Herman G. Berkman Chair in Diabetes Care Innovation
Barbara Helen Smith Chair in Preventive & Behavioral Medicine
Richard M. Haidack Professor in Medicine
There is a current project opening for using deep learning to train and ultimately perform automatic segmentation for multiple brain structures of interest in Multiple Sclerosis. Helpful background would include some proficiency in shell and Python. Please email me if interested.
Dr. Hemond is a board-certified neurologist with clinical subspecialty training in neuroimmunology and multiple sclerosis. His research focuses on the development and validation of MRI-based biomarkers to improve (1) early identification and (2) pathophysiological understanding of the neurodegenerative processes underlying MS.
Population and Quantitative Health Sciences
Biochemistry and Molecular Biotechnology
Prevention Research Center at UMass Chan
Healthcare Delivery and Population Sciences at UMass Chan - Baystate
Worcester Foundation for Biomedical Research Chair I
Preventing Osteoarthritis After an ACL Injury
Preventing Osteoarthritis After an ACL Injury Playing the Long Game: Consensus for Preventing OA
Preventing Osteoarthritis After an ACL Injury Playing the Long Game: Consensus for Preventing OA Characteristics of Accelerated Hand Osteoarthritis
Joseph D. Early Chair in Biomedical Research