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Immunology and Vascular Biology
Training Program
Summary
of Faculty Research
(Click on a highlighted name to view the faculty's homepage)
The Beutler lab is engaged in phenotype-driven analysis of all
genes required for robust resistance to microbial infection. Using
a random germline mutagen, mice with aberrant immune phenotypes
are generated and identified by methodical screening. When mutations
affecting immune function are detected, they are identified by positional
cloning. By starting with phenotype, the Toll-like receptors were
shown to be key sensors of microbial infection. Many of the key
events in Toll-like receptor signal transduction were then deduced.
Currently, trainees in the laboratory are attempting to find genes
that permit mice to contain infection by mouse cytomegalovirus (MCMV).
More than 300 genes with non-redundant function in MCMV resistance
probably exist, and among them, a large fraction will be proteins
with general importance to host immunity.
Rho GTPases control the assembly of the actin cytoskeleton, the production
of reactive oxygen species, and the activity of kinase cascades
mediating cell growth, death and motility. This spectrum of activities
places Rho GTPases as key components of such physiological and pathological
processes as tumor growth and metastasis, wound healing, neuronal
connectivity, inflammatory responses, angiogenesis, and development.
Our laboratory makes use of cellular, molecular, biophysical and
biochemical approaches to understand how the activities of Rho GTPases
are regulated, to identify the proteins they interact with to control
cell function, and to ascertain how these regulatory processes are
abnormal in various disease states.
The perception of man as the easy victor over microbes has changed dramatically
in the last decade. Vaccination has offered protection against a number of
viral pathogens, but it is increasingly recognized that the strategies used
in the past will not be successful against all viruses. More understanding
of viral pathogenesis and the interaction of viruses with the immune system
is required. This lab is focused on the interplay of antibodies and viruses
in humans. They make particular use of combinatorial antibody technology which
gives ready access to human antibodies. The viruses they are studying are
human immunodeficiency virus type 1 (HIV-1), respiratory syncytial virus (RSV)
and emerging viruses such as Ebola and hantavirus. Trainees will participate
in all aspects of this work including molecular biological, protein chemical,
virological and immunological studies.
Atherosclerosis is the focus of the work in my laboratory. Atherosclerosis
is a chronic inflammatory state in large and medium sized arteries
that can lead to acute cardiovascular events such as myocardial
infarction and stroke. To identify the key cellular and molecular
participants in this complex disease, we study the pathogenesis
of atherosclerosis in two popular gene knockout mice that have chronic
hyperlipidemia including low-density lipoprotein receptor- or apolipoprotein
E-deficient mice. Both innate and acquired immune responses contribute
to the vessel wall pathology of atherosclerosis. A proatherogenic
role for oxidized lipoproteins is well established. Multiple components
of oxidized lipoproteins can activate cells of both the innate and
acquired immune systems and influence disease outcome. The Toll
Like Receptors (TLR), which are important in microbial disease and
for their ability to initiate inflammatory responses, are major
players in atherosclerosis. More recently components of oxidized
lipoproteins have been shown to be TLR agonists. A postdoc in the
laboratory supported by this training grant recently reported a
role for TLR2-mediated inflammation. Endothelial cells mediate proatherogenic
inflammatory TLR2-mediated responses to unknown endogenous agonists
and may contribute to the regional specificity of lesion distribution
in the arterial tree. In contrast, the proatherogenic inflammatory
responses to known exogenous TLR2 agonists are mediated by macrophages.
Other trainees will conduct studies to support the idea that chronic
or recurrent microbial infections that activate TLR-mediated responses
contribute to the inflammation atherosclerotic disease. These studies
suggest the data suggest that host-derived endogenous TLR agonists
such as oxidized lipids can also influence disease progression.
Our lab investigates the factors which influence the generation
of the antibody repertoire in normal and in autoimmune mice. We
have shown that immunoglobulin gene segments are used in very different
frequencies, and some of our current research is aimed at elucidating
why this happens. We hypothesize that the accessibility of different
gene segments to the RAG recombinase may vary, and this may be determined
by the types and extent of covalent modifications to histone proteins
associated with the gene segments. We are thus doing detailed analyses
of these histone modifications in fetal and adult mice. We are also
interested in determining the role of key transcription factors
and cytokines in controlling accessibility to V(D)J recombination.
Other work in the lab addresses studies on the antibody repertoire
in lupus prone and diabetes prone mice. We have recent data showing
that receptor editing is not very efficient in lupus prone mice,
and we are exploring the reasons for this defect in B cell tolerance.
Our laboratory studies the role of actin dynamics in regulating assembly and function of the diverse cytoskeletal structures that contribute to cell and tissue morphogenesis during embryonic development. Current research focuses on tropomodulins (Tmods), a conserved family of actin pointed end-capping proteins that block association and dissociation at slow-growing (pointed) ends of actin filaments. Tmods also bind tropomyosins (TMs), which cooperate with Tmods to tightly cap actin pointed ends, regulating actin filament lengths and stability in the spectrin-based membrane skeleton of non-muscle cells and in the contractile myofibrils of skeletal and cardiac muscle. Differences among Tmod family members in expression patterns, TM isoform binding, and actin monomer and polymer regulation suggest unique functions for each of the four vertebrate Tmods. Recent studies of mouse knockouts further implicate key requirements for Tmods and TMs in diverse developmental processes, including striated muscle development, erythrocyte differentiation and stability, and eye lens fiber cell morphogenesis. A central question is: to what extent are common or distinct molecular mechanisms for Tmods’ regulation of actin dynamics utilized to drive unique features of morphogenetic differentiation and development in different tissues? We use a broad spectrum of approaches to answer these questions including molecular, cellular and functional analyses of development in transgenic mice, fluorescence confocal microscopy and 3D image analysis of the actin cytoskeleton in situ in mouse embryos, fluorescence imaging and biochemistry of actin organization and dynamics in cultured cells, and actin polymerization and binding assays with purified proteins in vitro .
Our laboratory also focuses on factors within human cells that attack HIV, immediately after its entry into the cytosol. These human restriction factors target the HIV capsid protein, which comprises the shell that surrounds and protects the viral genome. To circumvent these innate cellular defenses, HIV appears to have evolved the capacity to recruit the host cyclophilin A protein onto its capsid shell in order to successfully infect human cells. A profound understanding of the interplay between HIV and host cell factors is imperative in order to identify novel viral or cellular targets for the development of anti-HIV therapies.
The interests of my lab are centered on the basis of T cell activation through the T cell receptor during thymocyte development and the immune response. A major aspect of our current work is real-time imaging of molecular interactions during T cell activation, using fluorescent chimeras between cell surface or intracellular proteins and variants of the green fluorescent protein. Live cell deconvolution microscopy allows visualization of movements of these proteins into the immunological synapse during T cell activation, and, using fluorescence resonance energy transfer (FRET) between the fluorescent proteins, we can watch interactions between the proteins. During T cell activation, the T cell receptor must distinguish the few antigenic ligands from a vastly greater number of very similar, but non-stimulatory endogenous ligands. We have found that these non-stimulatory ligands in fact aid in the recognition of the antigenic ligand, and we are now seeking to understand the molecular basis of this phenomenon, as this is critical to understanding the basis of T cell activation. We recently discovered a new T cell specific protein that is necessary for T cell receptor-mediated signal transduction. The thymic positive selection process is defective in the absence of this gene, but the signaling pathway involved seems to be novel. Identifying how this molecule works is a new focus of the lab and is using a wide range of immunological, molecular genetic, biochemical and imaging tools.
Venous and arterial thrombosis contributes to morbidity and mortality
for many Americans. This laboratory is involved in long-term studies
of plasma proteins that regulate thrombosis and hemostasis. Networks
of mechanisms for up-regulation and down-regulation of thrombin
generation or of other coagulation factor proteases must act in
concert to prevent bleeding and yet avoid harmful blood clots. The
protein C pathway's key enzyme, activated protein C, provides physiologic
antithrombotic activity and remarkably also exhibits both anti-inflammatory
and anti-apoptotic activities. Biochemical, molecular biological,
and clinical research studies contribute to the laboratory's interdisciplinary
approach to define molecular mechanisms or defects that are related
to development of thrombosis and ischemic stroke. Animal model experiments
and clinical research studies are employed to assess the physiologic
or pathologic significance of molecular mechanisms that are defined
in vitro using purified proteins. Protein engineering is used to
establish structure-function relationships for clotting factors.
Using biochemical and clinical studies of plasma lipids and lipoproteins,
the laboratory is defining the anticoagulant activities and clinical
relevance of lipids and lipoproteins that modulate coagulation and
protein C pathways because of the strong epidemiologic association
between hyperlipidemia and hypercoagulability. The goal of our research
is to engage trainees fully in research that extends from bench
to bedside.
Dr. Han's research interests center on molecular events that occur in the
course of innate immune reactions. Over the last ten years, lipopolysaccharides
(LPS) activation in macrophages has been used to study intracellular
signaling pathways. A major contribution from this lab was the identification
of the p38 MAP kinase pathway, an essential signaling pathway in
inflammatory and other immune responses. Most of the core molecules
in this pathway, including p38 (or p38"), p38$, p38(, p38*,
MKK3, MKK6, and PRAK were identified and cloned in his laboratory.
A major goal is to understand the role of the p38 MAP kinase pathway
in macrophage activation. Using LPS-induced TNF production as an
endpoint of activation, the lab demonstrated that the p38 MAP kinase
pathway regulates TNF production at both transcriptional and post-transcriptional
levels. Recent exciting work shows that microRNA plays an essential
role in mRNA stability of cytokines. This laboratory is also interested
in the relationship between macrophage activation and macrophage
death. It was found that protein stability of MEF2 transcription
factor family members has a role in macrophage death after activation
with LPS and other stimuli. Stabilization of MEF2 transcription
factors in macrophages sensitizes macrophages to activation induced
cell death. The stability of MEF2 transcription factors is regulated
by the ubiquitin system and this system is likely to be regulated
by one or more caspases. As TNF is an important inflammatory mediator
of LPS responses, the mode of action of TNF is also studied using
a cell-based genetic approach. Using retrovirus insertion-mediated
random mutagenesis in cultured cells, genes that are critical for
TNF-induced cellular responses are identified. The retroviral vector
was specially designed to allow quick identification of disrupted
genes by 3'RACE. To date, 15 TNF-resistant clones with single gene
disruptions have been identified. Five of the ten genes have known
functions, while five do not. Trainees are involved in the identification
of the disrupted genes in all TNF-resistant clones and characterizing
their function in TNF-induced cellular responses.
The Kuhn Lab is developing novel therapeutics and diagnostics approaches
with a focus on cancer and viral infections. Research efforts focus
on i) the early detection and therapy management of cancer patients
and ii) the modulation of protein interactions for therapeutic intervention.
The approach is focusing on the developing and implementing innovative
technologies that detect and characterize cancer cells and other
rare cells in blood circulation. Results from this and other research
guides the structural proteomics drug discovery, which is utilizing
leading edge technologies in miniaturized structural genomics. Technological
examples of the work include a Rare Cell Detector for cancer diagnostic,
which is now in clinical trials and the implementation of the Compact
Light Source, the world's first small scale, high performance synchrotron
source for structural biology.
At least three collagen receptors figure prominently in the maturation
and differentiation of human megakaryocytes and in the adhesive
function of the platelets which they generate. This lab has directed
their research toward an analysis of these collagen receptors, the
integrin 1 1, the integrin 2 1 and the platelet-specific glycoprotein
VI (GPVI). The first goal of our research is to characterize the
regulation of the genes that encode these glycoproteins and their
role in megakaryocyte differentiation and platelet function. The
integrin 1 gene (ITGA1) and 2 gene (ITGA2) each encode a subunit
that directs specificity for collagens. Our aims are to characterize
the haplotype-specific control of ITGA2 expression in human and
murine megakaryocytes, and to characterize the lineage-specific
suppression of ITGA1 expression and the corresponding lineage-specific
enhancement of GP6 expression in megakaryocytes of both species.
A second goal of the research is to understand the relative contribution
of integrin 2 1 and GPVI during platelet adhesion to collagens and
the signal transduction that is initiated by the engagement of these
receptors. The lab has genetically engineered mice that are GP6-null
and will cross them with mice that lack ITGA2 gene expression. By
carefully analyzing the adhesive function and signal transduction
in platelets of double knockout mice and other progeny that express
intermediate levels of each receptor, they can sort out the contribution
of each receptor to platelet function and thrombus formation in
an intact animal model. The third goal of our research is to correlate
inheritance of human ITGA2 and GP6 haplotypes with risk for symptomatic
bleeding in von Willebrand Disease (VWD) types 1 and 2. From separate
studies of a large number of pedigrees containing index cases of
VWD type 1 or VWD type 2, the lab has already accumulated substantial,
statistically significant evidence for an association between increased
bleeding risk and those haplotypes of ITGA2 and GP6 that are biologically
related to decreased expression and/or activity of these receptors.
Further studies such as these in additional kindreds will corroborate
these findings and reveal the impact of these gene differences on
risk for adverse events in bleeding disorders such as VWD.
Research in Dr. Miles' laboratory addresses a paradigm in which interactions
of proteolytic systems with cell surfaces modulate cellular functions
and cells modulate protease systems via positive feedback mechanisms.
As a model protease system, the lab focuses on the plasminogen activation
system. Activation of this system results in generation of the broad
spectrum proteolytic activity of plasmin from the circulating, zymogen,
plasminogen. These studies in the laboratory have established a
key mechanism for regulating the broad spectrum proteolytic activity
of plasmin: localization of this system on cell surfaces, via binding
sites for both plasminogen and plasminogen activators. Localization
of the plasminogen activation system on cell surfaces results in
association of the broad spectrum proteolytic activity of plasmin
with the cell surface. It is increasingly being recognized that
cell surface association of plasmin is an essential feature of physiological
and pathological processes requiring extracellular matrix degradation
for cell migration including macrophage recruitment during the inflammatory
response, tissue remodeling, wound healing, tumor cell invasion
and metastasis and skeletal myogenesis. Trainee studies in the laboratory
are directed at understanding structural and functional mechanisms
that are responsible for the association of plasmin with cell surfaces,
using proteomics approaches as well as understanding the physiologic
function of plasminogen receptors, particularly in the inflammatory
response, using murine models.
Dr. Nemazee studies B lymphocyte receptor editing. The immune system eliminates
lymphocytes with antigen receptors reactive to self-tissue and promotes
the proliferation of cells that respond to foreign substances. We
have discovered that one way that autoreactive lymphocytes are eliminated
is not through cell death, but through an induced alteration of
their antigen receptor genes. During their development in the bone
marrow, immature B cells whose receptors bind antigens renew rearrangement
of the genes for antibody light chains, allowing the cells to alter
their antigen receptors and to lose self-reactivity. This process,
called "receptor editing," is apparently controlled at
the level of recombinase genes (RAGs). Recombinase genes can also
become reactivated during the immune response to foreign antigens.
Dr. Nemazee is trying to understand how signals from the antigen
receptor can control recombinase and how this regulation is rewired
at different stages of development.
The majority of adenovirus serotypes utilize the coxsackievirus-adenovirus
receptor (CAR) for virus-host cell attachment, but subgroup B and
subgroup D (adenovirus type 37 [Ad37]) viruses recognize CD46. CD46
is a ubiquitously expressed receptor that serves as a cofactor for
the inactivation of the complement components C3b and C4b, and it
also serves as a receptor for diverse microbial pathogens. A reported
consequence of CD46 engagement is a reduced capability of human
immune cells to express interleukin-12 (IL-12), a cytokine involved
in both the innate and adaptive immune responses. Studies were thus
undertaken to determine whether CD46-utilizing Ads alter the expression
of proinflammatory cytokines. Subgroup B (Ad16 and -35) and Ad37,
but not Ad2 or -5, significantly reduced IL-12 production by human
peripheral blood mononuclear cells stimulated with gamma interferon
(IFN-gamma ) and lipopolysaccharide. IL-12 mRNA (p35 and p40 subunits)
levels as well as other cytokine mRNA levels (IL-1 alpha and -beta,
IL-1Ra, and IL-6) were decreased upon interaction with CD46-utilizing
Ads. Analysis of transcription factor activity required for cytokine
expression indicated that CD46-utilizing Ads preferentially inhibited
IFN- -induced C/EBP protein expression, consequently reducing its
ability to form DNA complexes. Interference with IFN-gamma signaling
events by CD46-utilizing Ads, but not CAR-utilizing Ads, reveals
a potentially critical difference in the host immune response against
distinct Ad vectors, a situation that has implications for gene
delivery and vaccine development.
The Viral-Immunobiology Laboratory, under the direction of Michael Oldstone, is interested in understanding the molecular basis of how viruses infect cells, how the immune response aborts viruses, how viruses wrestle control away from the immune system to establish persistent infections, how persistent infection is initiated and maintained, and the mechanism of how such infections cause disease. Because viruses have different lifestyles, our studies focus on lessons taught primarily to three negative-strand viruses, lymphocytic choriomeningitis, measles and influenza viruses, and their interactions with the host's immune, nervous, and pulmonary system. The laboratory is also involved in prion disease pathogenesis.
My laboratory is conducting studies on the mechanism of human tumor metastasis using an in vivo model system that employs human tumor cells disseminating to specific organs in the developing chick embryo. A technique known as subtractive immunization is employed to generate in an unbiased manner unique antibodies directed against antigens on the surface of metastatic human tumor cells which are then tested for their ability to modulate metastatic spread. Tumor cell surface antigens that are functionally involved in metastasis are being identified by these methods. The quantitation of metastasis, using real time PCR with human specific primers, also has allowed for the in vivo selection and isolation of unique tumor cell variants from human fibrosarcomas and prostate and pancreatic carcinomas. Comparative analyses of the variants’ gene and protein expression levels are providing distinct information about metastasis-specific molecules.
The Reisfeld laboratory is developing novel approaches for anti-angiogenesis-based
immunotherapies of cancer with genomic vaccines targeting the tumor
vasculature and stroma. In collaboration with Linda Curtiss, this
anti-angiogenesis immunotherapy is also being used to suppress atherosclerotic
lesion progression.
The Ruf laboratory is interested in coagulation protease cell signaling
pathways and linkages to other signaling pathways in angiogenesis,
inflammation and thrombosis. Specific research directions are focused
on the cell biology of tissue factor (TF) and the role of protease
activated receptor (PAR) signaling specificity in angiogenesis and
inflammation. The lab uncovered an unexpected regulatory role of
TF in integrin signaling and is mapping out this signaling pathway
by defining with which integrins TF associates in tumor, endothelial
and immune cells. They are currently defining how adaptor recruitment
is regulated by phosphorylation of TF to establish the proximal
signaling complexes that link TF to integrins. Recently, the lab
defined a novel pathway of redox regulation of TF's extracellular
function that is expected to play a central role in the crosstalk
of TF with integrins. In other studies, the lab has provided evidence
for a crucial in vivo role of TF to regulate tumor and developmental
angiogenesis. The gain of function phenotype of TF cytoplasmic domain
deleted mice is employed to generate double knock-out mice with
potential intermediates of this pathway. The goal of these studies
is to map out this newly discovered signaling pathway and to define
new targets for therapeutic intervention in neovascular diabetic
eye diseases. Coagulation activation is closely linked to local
and systemic inflammatory processes in arthritis, bacterial sepsis
and viral hemorrhagic fevers. Coagulation protease-mediated signaling
through PARs has emerged as an important pathway by which the host
response to infection and inflammation is regulated. How protease
receptors, such as TF and EPCR, act as co-signaling receptors that
modify PAR signaling to regulate inflammation is studied. The lab
has generated new mouse models to test the role of coagulation protease
signaling in the crosstalk with the immune system. Trainees will
participate in the long term goal of these studies to define targets
downstream of protease signaling for intervention in inflammation
to complement or improve existing therapeutic strategies.
This laboratory is elucidating the structure and function of the
glycoprotein (GP) Ib-IX-V complex, a receptor with a key role in
platelet adhesion and aggregation under rapid blood flow conditions.
The proposed work is intended to: 1) elucidate the structural and
functional aspects of key components of the complex, including GP
Ib? and GP Ib?; 2) yield three-dimensional models based on x-ray
crystallography of the amino terminal domain of GP Ib? in complex
with ?-thrombin and the VWF A1 domain; 3) develop mouse models to
address questions relevant to the role of GP Ib-IX-V in thrombogenesis;
4) define in detail the functional consequences of specific interactions
of the GP-Ib-X-V complex with different substrates and agonists,
as well as the nature of the signaling networks that are evoked
upon engagement of the receptor and mediate cellular responses.
Additional studies are focused on the role played by VWF in initiating
platelet deposition at sites of vascular injury, particularly in
areas of the circulation characterized by rapid blood flow. The
laboratory is characterizing the biomechanical and structural properties
of the interaction between the VWF A1 domain and platelet GP Ib?;
the role of VWF multimers and membrane tethers in platelet adhesion
to surfaces exposed to rapidly flowing blood; the role of ?-thrombin
in modulating VWF binding to GP Ib?; the signaling events dependent
on the interaction between VWF A1 domain and GP Ib?; and defining
how VWF interacts with extracellular matrix components. A third
area involves the interplay of different constituents responsible
for the variable thrombogenicity of extracellular matrices and cell
surfaces exposed to flowing blood, and definition of the mechanisms
that regulate the response of platelets to such diverse stimuli.
The lab is involved in characterizing the different extracellular
matrix (ECM) components that induce platelet thrombus formation
at sites of vascular lesions, the distinct pathways of platelet
activation induced by different ECM components, regulation of platelet
reactivity with the surface of endothelial cells and other cells
of the vessel wall and the potential contribution of such mechanisms
to thrombus formation and evaluating the effects of targeted alterations
of ECM, cellular and platelet components on the process of thrombus
stabilization following a vascular lesion in vivo.
My laboratory is focused on understanding the mechanisms by which cells utilize the innate immune system to detect microbes and initiate defensive inflammatory responses. This work has three foci. First, we seek to understand the structural features of the Toll like receptors and their allied proteins LBP, CD14, and MD-2, which enable them to bind with high affinity to microbes and their components. Second, we seek to understand the structural changes by which binding of a microbial ligand to the extracellular domain of the receptor leads to signal transduction across the cell membrane and initiation of intracellular signaling cascades. Third, we seek to understand the involvement of microbial pathogen receptors in several inflammatory diseases including atherosclerosis.
Our research interests include the role of PU.1 and DMP1 transcription
factors in regulation of normal myeloid development and leukemogenesis
and hematopoietic cell gene delivery to block HIV-1 entry and limit
infection. The Torbett lab is identifying the myeloid transcriptional
factors that directly interact with the ets family transcription
factor, PU.1 (Sfpi1), to dictate neutrophil and monocyte/macrophage
differentiation. They demonstrated that disruption of PU.1 halts
myeloid differentiation at the myeloblast stage, and surprisingly,
endothelial development, without PU.1 no development to monocytes/macrophages
or dendritic cells occur. PU.1-null myeloblasts appear similar in
phenotype to the M2 stage found in human AML. To determine the consequence
of altered expression of PU.1 in committed myeloid lineages and
determine the panoply of PU.1 interacting transcription factors,
the lab is taking a have taken a proteomics approach to identify
PU.1 interacting partners and protein signaling pathways altered
when PU.1 is reduced or absent. Other work involves the cyclin D-interacting
myb-like protein (DMP1) transcription factor positively regulates
human p14ARF and CD13/ Aminopeptidase N (APN) expression, and plays
a role in cell-cycle control, differentiation and function of hematopoietic
and non-hematopoietic cells. p14ARF is critical for positive regulation
of p53, which in turns controls cellular proliferation and modulates
apoptosis. They identified two novel developmentally-expressed human
DMP1 splice variants (beta and gamma) of which beta functions as
a dominant-negative regulator of the originally reported DMP1 protein.
Given the role of DMP1 in ARF regulation and cellular proliferation
and our demonstration of a normally occurring DMP1 isoform that
functions as a dominant negative regulator of DMP1alpha, it is believed
that DMP1beta may have a role in contributing to loss of cell-cycle
control in selected classes of AML and CLL. Studies are focused
on molecularly defining the role of DMP1 isoforms in normal myeloid
development and selected leukemias. Finally this group has generated
improved HIV-1 vectors that are capable of sustained gene expression
in many primary human cell types. The biological and virological
effects of CCR5-intrabody genes and siRNA to CCR5 (a chemokine receptor
used as the main cellular portal for primary HIV-1 infection) delivered
by one of our HIV-1 vectors in primary stem cells and CD4 T cells
are being evaluated. Intracellular expression of CCR5-intrabody
or CCR5-siRNA restricts cell surface expression of the HIV-1 co-receptor
CCR5 and thus renders cell lines and primary cells expressing CCR5
resistant to infection by HIV-1s that utilizes CCR5 for entry.
The ultimate goal of our studies is to gain a deeper understanding of the molecular basis for important human diseases such as sudden death, heart attacks and HIV infection that cause substantial mortality and suffering. The structural details revealed by our work may provide clues for the design of more effective and safer medicines.
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