Science in Medicine
Abstract
Recent clinical and experimental studies are redefining the cellular and molecular bases of pulmonary arterial hypertension (PAH). The genetic abnormalities first identified in association with the idiopathic form of PAH — together with a vast increase in our understanding of cell signaling, cell transformation, and cell-cell interactions; gene expression; microRNA processing; and mitochondrial and ion channel function — have helped explain the abnormal response of vascular cells to injury. Experimental and clinical studies now converge on the intersection and interactions between a genetic predisposition involving the BMPR2 signaling pathway and an impaired metabolic and chronic inflammatory state in the vessel wall. These deranged processes culminate in an exuberant proliferative response that occludes the pulmonary arterial (PA) lumen and obliterates the most distal intraacinar vessels. Here, we describe emerging therapies based on preclinical studies that address these converging pathways.
Authors
Marlene Rabinovitch
Abstract
Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and is also linked to other neurologic and psychiatric disorders. FXS is caused by a triplet expansion that inhibits expression of the FMR1 gene; the gene product, FMRP, regulates mRNA metabolism in the brain and thus controls the expression of key molecules involved in receptor signaling and spine morphology. While there is no definitive cure for FXS, the understanding of FMRP function has paved the way for rational treatment designs that could potentially reverse many of the neurobiological changes observed in FXS. Additionally, behavioral, pharmacological, and cognitive interventions can raise the quality of life for both patients and their families.
Authors
Claudia Bagni, Flora Tassone, Giovanni Neri, Randi Hagerman
Abstract
There is an ever-growing demand for transplantable organs to replace acute and chronically damaged tissues. This demand cannot be met by the currently available donor organs. Efforts to provide an alternative source have led to the development of organ engineering, a discipline that combines cell biology, tissue engineering, and cell/organ transplantation. Over the last several years, engineered organs have been implanted into rodent recipients and have shown modest function. In this article, we summarize the most recent advances in this field and provide a perspective on the challenges of translating this promising new technology into a proven regenerative therapy.
Authors
Alejandro Soto-Gutierrez, Jason A. Wertheim, Harald C. Ott, Thomas W. Gilbert
Abstract
Spinal cord injury (SCI) is a devastating condition producing great personal and societal costs and for which there is no effective treatment. Stem cell transplantation is a promising therapeutic strategy, though much preclinical and clinical research work remains. Here, we briefly describe SCI epidemiology, pathophysiology, and experimental and clinical stem cell strategies. Research in stem cell biology and cell reprogramming is rapidly advancing, with the hope of moving stem cell therapy closer to helping people with SCI. We examine issues important for clinical translation and provide a commentary on recent developments, including termination of the first human embryonic stem cell transplantation trial in human SCI.
Authors
Andrea J. Mothe, Charles H. Tator
Abstract
Fanconi anemia (FA) is a rare genetic disorder associated with a high frequency of hematological abnormalities and congenital anomalies. Based on multilateral efforts from basic scientists and clinicians, significant advances in our knowledge of FA have been made in recent years. Here we review the clinical features, the diagnostic criteria, and the current and future therapies of FA and describe the current understanding of the molecular basis of the disease.
Authors
Younghoon Kee, Alan D. D’Andrea
Abstract
Lymphangioleiomyomatosis (LAM) is a rare progressive lung disease of women. LAM is caused by mutations in the tuberous sclerosis genes, resulting in activation of the mTOR complex 1 signaling network. Over the past 11 years, there has been remarkable progress in the understanding of LAM and rapid translation of this knowledge to an effective therapy. LAM pathogenic mechanisms mirror those of many forms of human cancer, including mutation, metabolic reprogramming, inappropriate growth and survival, metastasis via blood and lymphatic circulation, infiltration/invasion, sex steroid sensitivity, and local and remote tissue destruction. However, the smooth muscle cell that metastasizes, infiltrates, and destroys the lung in LAM arises from an unknown source and has an innocent histological appearance, with little evidence of proliferation. Thus, LAM is as an elegant, monogenic model of neoplasia, defying categorization as either benign or malignant.
Authors
Elizabeth P. Henske, Francis X. McCormack
Abstract
Addictive diseases, including addiction to heroin, prescription opioids, or cocaine, pose massive personal and public health costs. Addictions are chronic relapsing diseases of the brain caused by drug-induced direct effects and persisting neuroadaptations at the epigenetic, mRNA, neuropeptide, neurotransmitter, or protein levels. These neuroadaptations, which can be specific to drug type, and their resultant behaviors are modified by various internal and external environmental factors, including stress responsivity, addict mindset, and social setting. Specific gene variants, including variants encoding pharmacological target proteins or genes mediating neuroadaptations, also modify vulnerability at particular stages of addiction. Greater understanding of these interacting factors through laboratory-based and translational studies have the potential to optimize early interventions for the therapy of chronic addictive diseases and to reduce the burden of relapse. Here, we review the molecular neurobiology and genetics of opiate addiction, including heroin and prescription opioids, and cocaine addiction.
Authors
Mary Jeanne Kreek, Orna Levran, Brian Reed, Stefan D. Schlussman, Yan Zhou, Eduardo R. Butelman
Abstract
Stem cells are the critical unit affecting tissue maintenance, regeneration, and repair, with particular relevance to the tissues with high cell turnover. Stem cell regulation accommodates the conflicting needs of prompt responsiveness to injury and long-term preservation through quiescence. They are, in essence, the fundamental unit by which a tissue handles changing physiologic needs throughout the lifetime of the organism. As such, they are the focal point of dynamic tissue function, and their governance is physiology expressed at a cellular and molecular level. Here, we discuss the multiple components representing the stem cell niche in hematopoiesis and argue for a unbiased mapping of the niche constituents under different conditions as the first step in developing systems physiology.
Authors
Jonathan Hoggatt, David T. Scadden
Abstract
Our understanding of thyroid hormone action has been substantially altered by recent clinical observations of thyroid signaling defects in syndromes of hormone resistance and in a broad range of conditions, including profound mental retardation, obesity, metabolic disorders, and a number of cancers. The mechanism of thyroid hormone action has been informed by these clinical observations as well as by animal models and has influenced the way we view the role of local ligand availability; tissue and cell-specific thyroid hormone transporters, corepressors, and coactivators; thyroid hormone receptor (TR) isoform–specific action; and cross-talk in metabolic regulation and neural development. In some cases, our new understanding has already been translated into therapeutic strategies, especially for treating hyperlipidemia and obesity, and other drugs are in development to treat cardiac disease and cancer and to improve cognitive function.
Authors
Gregory A. Brent
Abstract
Alarmins are endogenous molecules that are constitutively available and released upon tissue damage and activate the immune system. Current evidence indicates that uncontrolled and excessive release of alarmins contributes to the dysregulated processes seen in many inflammatory and autoimmune conditions, as well as tumorigenesis and cancer spread. Conversely, alarmins have also been found to play a major role in the orchestration of tissue homeostasis, including repair and remodeling in the heart, skin, and nervous system. Here, we provide an update and overview on alarmins, highlighting the areas that may benefit from this clinical translation.
Authors
James K. Chan, Johannes Roth, Joost J. Oppenheim, Kevin J. Tracey, Thomas Vogl, Marc Feldmann, Nicole Horwood, Jagdeep Nanchahal
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Copyright © 2020 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)