JCI Online Early Table Of Contents: August 8, 2011
The development of drugs for brain-related conditions is not an efficient process; only 8% of candidate drugs that enter clinical trials gain FDA approval. A key reason for this low success rate is a lack of preclinical tests that accurately predict drug efficacy and detect unwanted side effects. But now, Jeremy Nathans and colleagues, at Johns Hopkins University School of Medicine, Baltimore, have developed a new preclinical approach that they hope can be used alongside current strategies to guide more efficient drug development for brain-related conditions.
In the study, Nathans and colleagues show that a wide variety of psychoactive compounds - sedatives; antipsychotic, antidepressant, and antiseizure drugs; and drugs of abuse, such as cocaine, morphine, and phencyclidine - induce characteristic alterations in eye movements in mice and that monitoring these changes can be used to rapidly and quantitatively assess the response of mice to these compounds. An example of the utility of this approach was demonstrated by its use to monitor disease progression in a mouse model of the neurodegenerative condition Huntington disease; the results suggest that it could be used to assess the effectiveness of candidate Huntington disease therapeutics.
TITLE: Preclinical assessment of CNS drug action using eye movements in mice
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
View this article at: http://www.jci.org/articles/view/45557?key=a22a0c604ac5a632a271
NEUROBIOLOGY: New insight into how lithium benefits patients with bipolar disorder
Bipolar disorder affects 1%-2% of the population worldwide. First-line therapy for this major psychiatric disorder is lithium. However, the identity of the molecular target via which lithium has beneficial effects in patients with bipolar disorder is highly controversial. A team of researchers, led by Peter Klein, at the University of Pennsylvania School of Medicine, Philadelphia, has now determined that in mice the protein GSK-3 is a critical target for lithium to mediate its effects on behavior. Furthermore, the team's analysis indicated that lithium works by preventing GSK-3 from joining the beta-arrestin-2/Akt/PP2A protein complex and stabilizing it. Defining the molecular target of lithium and its underlying mechanism of action could aid in the development of new therapies for bipolar disorder.
TITLE: Glycogen synthase kinase-3 is essential for beta-arrestin-2 complex formation and lithium-sensitive behaviors in mice
Peter S. Klein
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
View this article at: http://www.jci.org/articles/view/45194?key=0e6e60dddde18da0838b
OPHTHALMOLOGY: Reducing stress in the eye of benefit in glaucoma model
Glaucoma is the second most common cause of blindness in the United States. Primary open angle glaucoma (POAG) is the most common of the four forms of glaucoma, and the most common genetic cause of POAG is mutation of the MYOC gene. However, the mechanism underlying mutant MYOC-associated glaucoma has not been determined. New insight into this has now been obtained by a team of researchers, led by Val Sheffield, at the University of Iowa, Iowa City, through their analysis of transgenic mice that develop symptoms that closely resemble those seen in patients with POAG caused by a Y437H mutation in MYOC. A key observation made by Sheffield and colleagues was that the symptoms of glaucoma in the mice were associated with a cellular process known as ER stress and that reducing levels of ER stress alleviated the symptoms. These data suggest that targeting ER stress might provide a new approach to treating individuals with POAG.
TITLE: Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma
Val C. Sheffield
University of Iowa, Iowa City, Iowa, USA.
View this article at: http://www.jci.org/articles/view/58183?key=6d3da885a0ff73cd99cf
PULMONARY: Breath easier with the protein apelin
Pulmonary arterial hypertension (PAH) is the medical term given to increased pressure in the arterial blood vessels that carry blood from your heart to your lungs to pick up oxygen (the pulmonary arteries). PAH is a progressive disease that causes shortness of breath, tiredness, chest pain, and a racing heartbeat; it culminates in failure of the right side of the heart. There are no cures and a lung transplant is often necessary. Central to PAH are changes in the cells that line the pulmonary arteries (PAECs) that impair their function. A team of researchers, led by Marlene Rabinovitch, at Stanford University, Stanford, has now identified a new signaling pathway crucial to the survival of human PAECs that is disrupted in PAECs from patients with PAH. Central to this signaling pathway was upregulation of the protein apelin. As administration of apelin to mice reversed PAH, Rabinovitch and colleagues suggest that apelin could provide a new approach to treating PAH through its ability to rescue PAEC function.
TITLE: Disruption of PPAR-gamma/beta-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival
Stanford University, Stanford, California, USA.
View this article at: http://www.jci.org/articles/view/43382?key=f8802459de58ffd30e1e
IMMUNOLOGY: Take a TIM(id) approach to immune system modulation
The protein TIM-1 regulates the function of immune cells known as CD4+ T cells. However, its effects on other immune cell types have not been determined. Now, a team of researchers, led by David Rothstein, at the University of Pittsburgh School of Medicine, Pittsburgh, has identified in mice an important role for TIM-1 on immune cells known as B cells. Specifically, TIM-1 was found to mark a subpopulation of B cells that function to dampen immune responses (so called regulatory B cells). Furthermore, administration of a low-affinity antibody specific for TIM-1 to mice increased regulatory B cell numbers and these cells mediated acceptance of a genetically disparate pancreatic islet cell transplant. The team therefore suggests that targeting TIM-1 might provide a new therapeutic approach to modulating immune responses, for example following solid organ transplantation.
TITLE: Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice
David M. Rothstein
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
View this article at: http://www.jci.org/articles/view/46274?key=84b9bb1f2a4c53788551
CARDIOVASCULAR DISEASE: New human disease linked to the immune molecule IgE
The immune molecule IgE has a central role in causing allergy and asthma. But now, a team of researchers, led by Guo-Ping Shi, at Brigham and Women's Hospital and Harvard Medical School, Boston, has identified a role for IgE in atherosclerosis - a disease of the major arterial blood vessels that is one of the major causes of heart attack and stroke.
The initial analysis of Shi and colleagues indicated that IgE levels are elevated in patients who have had a heart attack or who have unstable angina (a symptom of atherosclerosis). Consistent with IgE having an effect on disease in these individuals, mice lacking one component of the protein complex to which IgE binds exhibited reduced atherosclerotic disease. Further analysis indicated that IgE impacted atherosclerotic development in mice via effects on cells that line arterial blood vessels and cells known as macrophages, which have a key role in the disease process. These data define a previously unrecognized role for IgE in human disease.
TITLE: IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe-/- mice
Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
View this article at: http://www.jci.org/articles/view/46028?key=1956c76c7c445c67c534
NEPHROLOGY: Key role for the protein KLF5 on the road to end-stage kidney disease
End-stage kidney disease is a growing clinical and economic burden that can only be treated through dialysis or a kidney transplant. Regardless of the site of the original kidney injury, damage to the tubules and interstitial tissue of the kidney (tubulointerstitial damage) is considered central to the progression of a kidney disease to end-stage disease. Work in mice, by Katsuhito Fujiu, Ichiro Manabe, and Ryozo Nagai, at the University of Tokyo, Japan, now provides new insight into how the inflammation that is crucial to tubulointerstitial damage is regulated. Specifically, Fujiu et al. find that expression of the protein KLF5 in the cells lining the collecting ducts of the kidney is essential for the inflammatory response that triggers damage in a mouse model of tubulointerstitial disease. These data have uncovered a previously unknown mechanism by which tubulointerstitial inflammation is regulated. Moreover, with further study, they could provide new targets for therapeutics that could slow the onset of end-stage kidney disease.
TITLE: Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice
Department of Cardiovascular Medicine, University of Tokyo, Bunkyo, Tokyo, Japan.
Department of Cardiovascular Medicine, University of Tokyo, Bunkyo, Tokyo, Japan.
View this article at: http://www.jci.org/articles/view/57582?key=453fa39d2a4115d0726c
DERMATOLOGY: CD4+ immune cells have a role in pemphigus
Pemphigus vulgaris is a painful condition that involves blistering of the skin and mucous membranes. It is an autoimmune disease because it is caused by immune molecules known as antibodies that have turned on a protein critical to the individual's health, an adhesion protein crucial for maintaining the integrity of the skin and the lining of the mouth and esophagus (Dsg3). A team of researchers, led by Masayuki Amagai, at Keio University School of Medicine, Japan, has now determined that CD4+ T cells that recognize Dsg3 can also induce pemphigus-like symptoms in mice as well as a distinct form of skin inflammation known as interface dermatitis, which is a feature of various inflammatory/autoimmune skin diseases. These data provide new insight into the immune mechanisms underlying pemphigus, and the mice generated for the study will act as valuable tools in further understanding the role of CD4+ T cells in skin diseases.
TITLE: Desmoglein 3-specific CD4+ T cells induce pemphigus vulgaris and interface dermatitis in mice
Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
View this article at: http://www.jci.org/articles/view/57379?key=3455961338ca680b0a14