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Peroxisome proliferator-activated receptor-γ and its agonists in hypertension and atherosclerosis: Mechanisms and clinical implications

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American Journal of Cardiovascular Drugs 2005年第6期5卷 389-398页

作者： Halabi, Carmen M. Sigmund, Curt D. Medical Scientist Training Program and Genetics Program University of Iowa Iowa City IA United States Department of Internal Medicine University of Iowa Iowa City IA United States Department of Physiology and Biophysics University of Iowa Iowa City IA United States Departments of Internal Medicine and Physiology and Biophysics Roy J. and Lucille A. Carver College of Medicine University of Iowa Iowa City IA 52242 United States

Cardiovascular diseases are the leading cause of morbidity and mortality in the US. Proper management and/or prevention of atherosclerosis and hypertension, two complex and chronic disorders, would significantly reduce the risk for cardiovascular events such as myocardial infarction and stroke, but this requires an understanding of the mechanisms underlying their development and progression. Whereas a great deal has been learned and applied toward the management of these disorders, especially hypertension, morbidity and mortality remains unacceptably high, most likely because there are disease-causing mechanisms that have yet to be fully recognized. Understanding these disease mechanisms is necessary so that novel management strategies can be developed. One of these novel mechanisms centers on peroxisome proliferator-activated receptor (PPAR)-γ. PPAR-γ is a member of the nuclear receptor superfamily of ligand-activated transcription factors known to play a role in glucose homeostasis and adipocyte differentiation and, more recently, has been shown to have anti-inflammatory, antiatherogenic, and antihypertensive effects. Thiazolidinediones, a class of drugs used in the treatment of type 2 diabetes mellitus, are high-affinity ligands for PPAR-γ. In this review, the anti-inflammatory, anti-atherosclerotic, and anti-hypertensive mechanisms by which PPAR-γ and its agonists are thought to exert protective effects on the cardiovascular system are discussed. Ongoing clinical trials using PPAR-γ activators for the management of cardiovascular diseases, especially in patients with type 2 diabetes mellitus, are summarized. © 2005 Adis Data Information BV. All rights reserved.

关键词： Alkanesulfonates Animals Atherosclerosis Clinical Trials Clofibric Acid Humans Hypertension Mice Mice Knockout Models Animal PPAR gamma Phenylpropionates Research Support N.I.H. Extramural Thiazolidinediones

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Multivariate curve resolution on two-photon fluorescence images of human skin

Multivariate curve resolution on two-photon fluorescence ima...

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European Congress on Computational Methods in Applied Sciences and Engineering, ECCOMAS 2004

作者： Tkaczyk, Eric R. Laiho, Lily H. So, Peter T. Medical Scientist Training Program 2965 Taubman Medical Library University of Michigan 1150 W. Medical Center Drive Ann Arbor MI 48109-0619 United States Cambridge MA 02139 United States

Two-photon fluorescence microscopy has been demonstrated as a high-resolution 3-D tissue imaging technique. If the dream of a noninvasive optical biopsy is to be realized upon this technology, biochemically relevant information must be extracted from the data thus obtained. The current study investigated the ability of different Gram-Schmidt modifications to Orthogonal Projection Multivariate Curve Resolution (MCR) to find the emission spectra and distributions of fluorophores in volume images. A two-photon microscope, incorporating a high-power femtosecond Ti: Sapphire laser and a high sensitivity multianode photomultiplier spectrally resolved detector, was used to obtain spectroscopic data for each point in a volume of the sample. The MCR algorithm was developed and tested by first examining fluorescent beads. MCR analysis on images obtained from ex vivo human skin provided recognizable structural resolution with no a priori information, suggesting that the resolved spectra correspond to different endogenous fluorophores.

关键词： Harmonic generation

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Ethics in population-based genetic research

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Accountability in Research 2004年第1期11卷 1-26页

作者： DeCamp, Matthew Sugarman, Jeremy Duke University Medical Scientist Training Program School of Medicine Department of Philosophy Durham NC United States Phoebe R. Berman Bioethics Institute Johns Hopkins University Baltimore MD United States

Population-based genetic research, including genetic epidemiology, shows tremendous potential to elucidate the role of genes as causal factors in complex and common human diseases. Like all research with human subjects, full realization of these benefits requires careful attention to its ethical conduct, establishing an appropriate balance between individual protections and the advancement of scientific and medical knowledge. This article reviews the growing literature on genetics research and ethics to describe some of the fundamental ethical issues in population-based genetics research, including research design, recruitment and informed consent, and dealing with research results. Its focus is on areas where consensus is forming and where future work is needed. © Taylor & Francis Inc.

关键词： Ethics Genetics research Informed consent Population genetics Research standards Research subjects

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Topical Review: Neuronal Migration in Developmental Disorders

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Journal of Child Neurology 2004年第3期19卷 280 - 286页

作者： Matthew F. McManus Jeffrey A. Golden Neuroscience Program University of Pennsylvania School of Medicine Philadelphia PA Medical Scientist Training Program University of Pennsylvania School of Medicine Philadelphia PA Neuroscience Program University of Pennsylvania School of Medicine Philadelphia PA . Department of Pathology Children's Hospital of Philadelphia Philadelphia PA Department of Pathology University of Pennsylvania School of Medicine Philadelphia PA

Normal central nervous system development is dependent on extensive cell migration. Cells born in the proliferative ventricular zone migrate radially along specialized glial processes to their final locations. In contrast, most inhibitory interneurons found in the adult mammalian cerebral cortex and some other structures migrate along a nonradial pathway and on substrates only recently defined. Defects in radial cell migration have been implicated in several distinct human syndromes in which patients often present with epilepsy and mental retardation and have characteristic cerebral abnormalities. The identification of several genes responsible for human neural cell migration defects has led to a better understanding of the cellular and molecular interactions necessary for normal migration and the pathogenesis of these disorders. The prototypic cell migration disorder in humans is type I lissencephaly. Although type 1 lissencephaly is clearly a defect in radial cell migration, recent data from two model systems (Lis1 and ARX mutant mice) indicate that a defect in non—radial cell migration also exists. Thus, the result of a LIS1 mutation appears to have broader implications than a radial cell migration defect alone. Furthermore, it is likely that the observed defect in non—radial cell migration contributes to the clinical phenotype observed in these patients. Herein we discuss the role of normal non—radial cell migration in cortical development, as well as how perturbations in both radial and nonradial migration result in developmental anomalies. (J Child Neurol 2005;20:280—286).

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Quantitative analysis of membrane protein localization and signaling

Quantitative analysis of membrane protein localization and s...

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Proceedings - 2004 IEEE Computational Systems Bioinformatics Conference, CSB 2004

作者： Kasson, Peter M. Huppa, Johannes B. Davis, Mark M. Brunger, Axel T. Biophysics Program Stanford CA 94305 Medical Scientist Training Program Stanford CA 94305 Department of Molecular Physiology Stanford CA 94305 Department of Microbiology Stanford CA 94305 Stanford Synchrt. Radiat. Laboratory Stanford University Stanford CA 94305 Howard Hughes Medical Institute Stanford CA 94305

ISBN: (纸本)0769521940

Fluorescence microscopy of labeled proteins yields a wealth of data on cell signaling processes. However, systems for quantitative analysis of such data have lagged behind the recent progress in data acquisition technology. As cellular protein redistribution plays a key role in proximal signaling and the establishment of cell polarity, quantitative information is critical for understanding many signaling networks. We have developed a robust automated system to analyze membrane protein redistribution based on datasets obtained via fluorescence video microscopy. Our system provides methods for cell surface segmentation and reconstruction, cell shape tracking, cell-surface parameterization, and cluster formation analysis. Our system is novel in both its integration and its surface-based approach, enabling model-free analysis of protein redistribution across the entire cell. We validate our system by measuring receptor clustering in T lymphocytes undergoing activation, obtaining clustering velocities consistent with the previously reported single-particle tracking data that serve as our reference standard. Our methods generalize to many cell-signaling phenomena, allowing quantitative measurement of these cell membrane processes and offering the ability to derive empiric parameters for spatial signaling network models.

关键词： Proteins

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Quantitative analysis of lymphocyte membrane protein redistribution from fluorescence microscopy

Quantitative analysis of lymphocyte membrane protein redistr...

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2004 International Conference on Image Processing, ICIP 2004

作者： Kasson, Peter M. Huppa, Johannes B. Davis, Mark M. Brunger, Axel T. Biophysics Program Stanford CA 94305 Medical Scientist Training Program Stanford CA 94305 Department of Molecular and Cellular Physiology Stanford CA 94305 Department of Microbiology and Immunology Stanford CA 94305 Stanford Synchrotron Radiation Laboratory Stanford University Stanford CA 94305 Howard Hughes Medical Institute Stanford CA 94305

The relocalization of plasma membrane proteins is critical for establishing cellular polarity and regulating cell signaling. Three-dimensional fluorescence video microscopy allows the dynamic visualization of proteins in living cells. We have developed a robust and automated method to employ fluorescence data acquired in this manner for quantitative analysis of membrane protein movements across the cell surface. Our method utilizes level-set-based surface reconstruction followed by a maximum likelihood surface registration algorithm for rigid-body alignment of noisy images. A surface-walking technique yields distance maps for the cell surface, which are then used to measure changes in protein surface distribution over time. Applying this method to signaling in T lymphocytes, we have used it to monitor receptor movements and have validated these results against previously reported single-particle tracking data. ©2004 IEEE.

关键词： Proteins

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Ethics and research assessing the relative roles of genes and the environment

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Accountability in Research 2004年第3-4期11卷 161-182页

作者： DeCamp, Matthew Sugarman, Jeremy Duke University Medical Scientist Training Program School of Medicine and Department of Philosophy Durham NC United States Phoebe R. Berman Bioethics Institute Johns Hopkins University Baltimore MD United States

Research on the interaction of genes and the environment is revealing that many human diseases have both genetic and environmental components. Even traditional "environmental" diseases, such as infections, appear to interact with genetic components in the human host. Environmental genetics research will inevitably increase understanding of individual susceptibilities to toxic exposures in the environment and harmful side effects of medications;therefore, it has great promise for improving the prevention and treatment of human diseases. However, realizing the benefits of this research requires careful attention to ethical issues that are particularly relevant in this context. This article reviews some of the most pressing issues related to research design and methods, as well as from the application of research results (e.g., workplace genetic screening and legal toxic torts, personal medical responsibility, and the relationship between genetics and public health measures). © Taylor & Francis Inc.

关键词： Environmental genetics Ethics Genetic research Population genetics Research standards Research subjects

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PHR1, a PH Domain-Containing Protein Expressed in Primary Sensory Neurons

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Molecular and Cellular Biology 2004年第20期24卷 9137-9151页

作者： Shunbin Xu Yanshu Wang Haiqing Zhao Lilei Zhang Weihong Xiong King-Wai Yau Hakim Hiel Elisabeth Glowatzki David K. Ryugo David Valle 1 Howard Hughes Medical Institute2 McKusick-Nathans Institute of Genetic Medicine 1 Howard Hughes Medical Institute3 Department of Molecular Biology and Genetics 2 McKusick-Nathans Institute of Genetic Medicine4 Predoctoral Training Program in Human Genetics 5 Department of Neuroscience 1 Howard Hughes Medical Institute5 Department of Neuroscience 6 Department of Otolaryngology Johns Hopkins University School of Medicine Baltimore Maryland 5 Department of Neuroscience6 Department of Otolaryngology Johns Hopkins University School of Medicine Baltimore Maryland

Previously, we identifiedPHR1as an abundantly expressed gene in photoreceptors and showed that it encodes four isoforms, each with N-terminal pleckstrin homology (PH) and C-terminal transmembrane domains. To better understandPHR1function and expression, we made aPhr1null mouse by inserting a β-galactosidase/neorcassette into exon 3. In addition to photoreceptors, we found abundant expression of specificPhr1splice forms in olfactory receptor neurons and vestibular and cochlear hair cells. We also foundPhr1expression in cells with a possible sensory function, including peripheral retinal ganglion cells, cochlear interdental cells, and neurons of the circumventricular organ. Despite this discrete expression in known and putative sensory neurons, mice lackingPHR1do not have overt sensory deficits.

关键词： .homology cassette photoreceptors Olfactory ganglion Howard Hughes medical Primary Sensory PHR PH Domain-Containing pleckstrin Phr expression

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Rational design of peptide vaccines for autoimmune disease: Harnessing molecular recognition to fix a broken network

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Expert Review of Vaccines 2003年第1期2卷 61-73页

作者： Weathington, Nathaniel M. Blalock, J. Edwin Medical Scientist Training Program Department of Physiology University of Alabama Birmingham AL 35294 1918 Univ. Blvd United States Department of Physiology University of Alabama McCallum Basic Hlth. Sci. Bldg. 898 Birmingham AL 35294 1918 Univ. Blvd United States

Autoreactive T-cells and antibodies are found at low levels in normal individuals and are thought to be kept at bay by regulatory T-cells and a network of idiotypic and antiidiotype-bearing antigen receptors on lymphocytes as well as idiotypic anti-idiotypic antibodies. Disruption of this network by genetic, environmental and unknown factors is thought to result in autoimmune diseases. An obvious, ideal and specific therapy for such disorders would be to harness this regulatory network to re-establish immunologic homeostasis. In practice, however, this is not an easy task as most autoimmune diseases involve polyclonal responses to self antigen. Thus, we are faced with the conundrum of not knowing which autoreactive idiotype-bearing antibody or antigen receptor(s) to target in order to restore or Induce network regulatory function. The thesis of this review is that understanding a fundamental property governing peptide/protein shape can be used in part to circumvent the problems of self reactivity and polyclonality in autoimmune disorders. More specifically, an algorithm has been developed to design peptide vaccines with shapes that are thought to be complementary in contour to self epitopes which seem to be the focus of autoimmunity. In theory, such complementary shapes should be engendered in certain autoreactive antigen receptors - these complementary constructs consequently represent receptor mimetics. By targeting an immune response against such mimetics, one generates a polyclonal anti-idiotype response that matches the complexity of the autoimmune response itself. This article will describe the algorithm for vaccine design, summarize the in vitro and in vivo evidence for its efficacy and discuss possible therapeutic utility in human autoimmune diseases.

关键词： Anti-idiotypic antibody Complementary peptides Giullan Barre's syndrome Immune network Multiple sclerosis Myasthenia gravis Sjogren's syndrome Systemic lupus erythematosus T-cell receptor

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SLP-76 regulates Fcγ receptor and integrin signaling in neutrophils

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Immunity 2003年第5期19.0卷 761-769页

作者： Newbrough, Sally A. Mocsai, Attila Clemens, Regina A. Wu, Jennifer N. Silverman, Michael A. Singer, Andrew L. Lowell, Clifford A. Koretzky, Gary A. Abramson Fam. Cancer Res. Institute University of Pennsylvania Philadelphia PA 19104 United States Medical Scientist Training Program University of Pennsylvania Philadelphia PA 19104 United States Department of Laboratory Medicine Univ. of California San Francisco San Francisco CA 94143 United States Dept. of Pathol./Laboratory Medicine University of Pennsylvania Philadelphia PA 19104 United States Department of Physiology Semmelweis University School of Medicine Budapest Hungary

While the contribution of intracellular adaptor proteins to lymphocyte activation has been well studied, the function of these molecules in innate immune effector cells such as neutrophils has not been extensively addressed. Here we demonstrate a critical role for the adaptor molecule SH2 domain-containing leukoctye-specific phosphoprotein of 76 kDa (SLP-76) in FcγR and integrin signaling. Stimulation of these receptors induces tyrosine phosphorylation and cytoplasmic relocalization of SLP-76 in freshly isolated murine neutrophils. Neutrophils lacking SLP-76 demonstrate decreased FcγR-induced calcium flux and reactive oxygen intermediate (ROI) production in response to immune complex stimulation. More dramatically, SLP-76^-/- neutrophils fail to produce ROI, spread, or activate critical downstream regulators in response to integrin ligation. These results provide genetic evidence for a critical role of SLP-76 in the regulation of neutrophil function.

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