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News From The Journal Of Clinical Investigation: June 18, 2012

AGING Preventing cellular aging and aging-related degenerative diseases

Age-associated degeneration is caused, at least in part, by accumulated cellular damage, including DNA damage, but how these types of damage drive aging remains unclear. Dr. Paul Robbins and colleagues at the University of Pittsburgh sought to address this question using a mouse model of DNA repair deficiency. The Robbins team found that DNA damage drives aging, in part, by activating NF-κB, a transcription factor that responds to cellular damage and stress. They report that inhibition of NF-κB reduces oxidative stress, oxidative DNA damage, oxidative protein damage, and cellular senescence induced by oxidative damage. Their data suggest that NF-κB inhibitors can mitigate cellular damage and could provide clinical benefit for degenerative changes caused by aging.

TITLE: NF-κB inhibition delays DNA damage-induced senescence and aging in mice


IMMUNOLOGY Combatting fungal eye infections

Pathogenic fungal infections of the eye can be difficult to treat and often result in blindness. Sixto Leal, Eric Pearlman, and colleagues at Case Western Reserve University have investigated the cellular warfare occurring between fungi and the immune system during eye infections. They employed mouse model systems to investigate the involvement of neutrophils, the first immune cell type at sites of injury, in controlling fungal infections. Their results showed that neutrophils are critical to controling fungal infections of the eye. The team subsequently examined how neutrophils effectively kill fungi. They determined that in a specific enzyme, called NADPH oxidase, kills fungi. In parrallel, mutated fungal strains were used to determine how fungi fight back against the immune system, demonstrating that specific fungal genes protect against NADPH produced by neutrophils. Furthermore, they showed that a drug known as PX-12 enhanced the ability of neutrophils to kill infectious fungus. Understanding the interactions between host and pathogen can provide new insight for designing better fungal infection treatments, in hopes of ultimately reducing the prevalence of infectious blindness.

TITLE: Thioredoxin and superoxide dismutase mediate fungal survival against neutrophil oxidation


NEUROBIOLOGY Molecular effects of social isolation on neurotransmission

Social isolation in early childhood has been linked to depression, addiction, and anxiety disorders. Work in animal models has shown that early postnatal experiences are vital for organization in the developing cerebral cortex, which can be perturbed by stress. Dr. Takuya Takahashi at Yokohama City University Graduate School of Medicine set out to describe the effects of neonatal stress, particularly stress caused by isolation, on the molecular events that determine the circuitry of the brain. In rodents, the effects of whisker experience, a major conduit of social interaction, can be directly identified in a specific sensory nerves in the barrel cortex region. Whisker experience drives the delivery of specific receptors, known as AMPA receptors, to the receiving end of neuronal synapses where they bind to glutamate and mediate synaptic transmission. The Takahashi team reported that isolating pups from their mothers for even a few hours a day reduced the delivery of AMPA receptors to neuronal synapses. Isolation increased systemic levels of active corticosterone, a glucocorticoid associated with stress. The group found that corticosterone injection mimicked the molecular effects of social isolation, and blocking glucocorticoid receptors with an antagonist prevented them. Their study provides preclinical data supporting glucocorticoid receptor antagonists as therapeutics and suggests continued studies of the molecular changes associated with early traumatic experience may lead to the identification of useful biomarkers for mental disorders.

TITLE: Disrupted cortical function underlies behavior dysfunction due to social isolation


CARDIOLOGY Imaging immune cell recruitment into the beating heart

Two-photon microscopy is an imaging technique that captures single-cell motion in living organisms and has been widely utilized in the study of inflammatory responses. However, this technique has not proven effective for studying moving tissues, including heart muscle. Drs. Daniel Kreisel and Mark Miller, along with colleagues at the Washington University School of Medicine and the National Institutes of Health, now report a method for the real-time imaging of recruitment of immune cells known as leukocytes in beating mouse hearts following cardiac injury. Using this approach, they visualized neutrophils clustering in heart muscle tissue after coronary artery blockage or heart transplantation. The team also observed reduced neutrophil migration after injury when ICAM-1 signaling, known to be important for neutrophil recruitment, was inhibited. This approach represents an important development in imaging techniques and holds particular promise for studying the role of inflammation in cardiovascular disease.

TITLE: Intravital 2-photon imaging of leukocyte trafficking in beating heart


HEMATOLOGY Understanding mutations that underlie congenital anemia

Diamond-Blackfan anemia is a congenital form of anemia due to low red blood cell counts. To date, approximately half of all cases of Diamond-Blackfan anemia have been attributed to ribosomal protein gene mutations. Dr. Hanna Gazda and colleagues at Harvard University in Boston performed a detailed analysis of gene expression on two siblings with Diamond-Blackfan anemia who had no known disease-causing mutations. The Gazda team identified a mutation in the gene encoding the hematopoietic transcription factor GATA1 that impairs production of the full-length form of the protein. Their findings provide insight into the development of Diamond-Blackfan anemia and shows that the disease can arise from causes other than defects in ribosomal protein genes. The identified mutations also illustrate the critical role for GATA1 in human blood cell production.

TITLE: Exome Sequencing Identifies GATA1 Mutations Resulting in Diamond-Blackfan Anemia




CARDIOLOGY Genetic cause of cardiac conduction disturbances revealed

Heart contraction patterns rely on proper conduction of electrical impulse, and disturbances of cardiac conduction are associated with arrhythmias and cardiac arrest. The pattern of conduction depends on appropriate regulation of gene expression by key transcription factors and transcriptional enhancers. Dr. Vincent Christoffels and colleagues at the University of Amsterdam in the Netherlands conducted an extensive study to characterize in cardiac cells where in the mouse genome key cardiac transcription factors, including TBX3, NKX2-5 and GATA4, bind in heart. They identified new regulatory elements, known as gene enhancers, in ion channel genes, such as the Scn5a/Scn10a locus that was bound by TBX3. The Christoffels team went on to show that a single-nucleotide polymorphism in the SCN10A enhancer, associated with alterations in cardiac conduction patterns in humans, disrupts TBX3 binding and reduces the cardiac activity of the enhancer. Their work identifies key regulatory elements for cardiac conduction and helps to explain how genetic variants in non-coding DNA sequences influence cardiac conduction and risk of cardiac arrhythmias.

TITLE: Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer


NEUROBIOLOGY Disrupted adenosine signaling contributes to schizophrenia

An emerging concept in schizophrenia posits that abnormal adenosine signaling might underlie disease development. Dr. Detlev Boison and colleagues at Legacy Research in Portland, Oregon designed experiments to test the ‘adenosine hypothesis’ of schizophrenia with pharmacological and molecular tools, and to evaluate novel adenosine-based strategies for therapeutic intervention. The Boison team found that augmenting adenosine by pharmacological inhibition of adenosine kinase (ADK), the key enzyme for metabolic adenosine clearance, exerted antipsychotic-like activity in mice, whereas transgenic overexpression of ADK was associated with attentional impairments linked to schizophrenia. By perturbing adenosine release in two different regions of the mouse brain, the group went on to show disrupting adenosine production in either the striatal and hippocampal regions contributed to schizophrenia-relevant symptoms, and suggests that developing local adenosine augmentation therapies might be effective for the treatment of schizophrenia.

TITLE: Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia in mice


ONCOLOGY Chemosensitivity is controlled by transcription factor modification

The development of targeted cancer treatments that increase tumor chemosensitivity is important for improving therapy. Several chemotherapeutic drugs increase levels of ISG15, a ubiquitin-like protein that can be bound to other cellular proteins to modify their function, suggesting that ISGylation may inhibit cancer . However, how ISGylation of specific target proteins controls tumorigenesis is poorly understood. Dr. Chin Ha Chung and colleagues at the Seoul National University identified proteins that are ISGylated in response to chemotherapy. They found that an isoform of a transcription factor known as p63 was ISGylated and that this modificaton played an essential role in downregulating its activity. Anticancer drugs induced ISGylation of this p63 isoform, which blocked its ability to promote tumor formation. Their findings provide the first demonstration that ISG15 is a tumor suppressor through its conjugation to p63.

TITLE: Chemosensitivity is controlled by p63 modification with ubiquitin-like protein ISG15



Journal of Clinical Investigation