EDITOR'S PICK: Comfort food: probiotic-derived product protects in model of intestinal inflammation
Many people tout the beneficial effects of probiotics in preventing and/or treating several intestinal diseases, including ulcerative colitis. Although there have been few, if any, good clinical studies evaluating the clinical efficacy of probiotics, preclinical data suggest that probiotics and approaches utilizing probiotic-derived products could be effective therapies for acute and chronic gastrointestinal disorders. In this context, a team of researchers, led by Fang Yan, at Vanderbilt University Medical Center, Nashville, have now identified a new probiotic bacteria–derived soluble protein that can protect intestinal cells from inflammation and injury and unraveled its mechanism of action. Importantly, specific delivery of the protein (p40) to the colon provided therapeutic and prophylactic protection in several mouse models of colitis. The authors suggest that their data provide rationale for the development of probiotic-derived proteins as reagents for preventing and/or treating ulcerative intestinal inflammatory disorders.
In an accompanying commentary, Fayez Ghishan and Pawel Kiela, at the University of Arizona, Tucson, concur with this position, although they caution that further work in humans is needed.
TITLE: Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism
AUTHOR CONTACT:
Fang Yan
Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Phone: 615.343.5021; Fax: 615.343.5323; E-mail: fang.yan@vanderbilt.edu.
View this article at: http://www.jci.org/articles/view/44031?key=24d663bbebde11d8c23d
ACCOMPANYING COMMENTARY
TITLE: From probiotics to therapeutics: another step forward?
AUTHOR CONTACT:
Fayez K. Ghishan
University of Arizona, Tucson, Arizona, USA.
Phone: 520.626.5170; Fax: 520.626.7176; E-mail: fghishan@peds.arizona.edu.
View this article at: http://www.jci.org/articles/view/58025?key=9172d5ef2e96a5eda4f0
NEPHROLOGY: Complex inhibition of severe complication of diabetes
Diabetic nephropathy is a serious, sometimes lethal, complication of diabetes (both type 1 and type 2 diabetes). The prevalence of this devastating progressive kidney disease, which often leads to the need for dialysis or kidney transplantation, is increasing, making it a major public health problem in modern society. Understanding the molecular mechanisms underlying the condition is crucial if new therapies for its treatment and prevention are to be developed. In this context, two research groups (one led by Ken Inoki, at the University of Michigan, Ann Arbor, and Kun-Liang Guan, at the University of California at San Diego, La Jolla; and the other led by Tobias B. Huber, at University Hospital Freiburg, Germany), working with genetically engineered mice, have now determined that inhibiting a molecular complex known as mTORC1 in kidney cells known as podocytes might provide a new way to prevent progressive diabetic nephropathy.
As pointed out by Agnes Fogo, at Vanderbilt University, Nashville, in an accompanying commentary, it will be important to establish in animal models how much mTORC1 inhibition is most beneficial and at what stage of the disease, as data from both groups indicates that too little or too much mTORC1 activity can be deleterious to podocytes and that the effects can be age-dependent.
TITLE: mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice
AUTHOR CONTACT:
Ken Inoki
University of Michigan, Ann Arbor, Michigan, USA.
Phone: 734.763.1102; Fax: 734.647.9702; E-mail: inokik@umich.edu.
Kun-Liang Guan
University of California at San Diego, La Jolla, California, USA.
Phone: 858.822.7945; Fax: 858.822.5433; E-mail: kuguan@ucsd.edu.
View this article at: http://www.jci.org/articles/view/44771?key=8d635a788ef4d5933ecf
ACCOMPANYING ARTICLE
TITLE: Role of mTOR in podocyte function and diabetic nephropathy in humans and mice
AUTHOR CONTACT:
Tobias B. Huber
University Hospital Freiburg, Freiburg, Germany.
Phone: 49.761.270.3559; Fax: 49.761.270.3270; E-mail: tobias.huber@uniklinik-freiburg.de.
View this article at: http://www.jci.org/articles/view/44774?key=013ff9feb01aae2b97dc
ACCOMPANYING COMMENTARY
TITLE: The targeted podocyte
AUTHOR CONTACT:
Agnes B. Fogo
Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Phone: 615.322.3070; Fax: 615.343.7023; E-mail: agnes.fogo@vanderbilt.edu.
View this article at: http://www.jci.org/articles/view/57935?key=5290bb27a0886290d080
OPHTHALMOLOGY: The all-seeing eye: broad insight into genetic eye disease
Leber congenital amaurosis (LCA) is a rare eye disease that severely affects vision at a very young age, usually from birth. It is caused by mutations in any one of at least 15 genes. Two groups of researchers have now generated important new data on LCA. As noted in an accompanying commentary by José-Alain Sahel, at the Pierre and Marie Curie Medical School-Paris, France, these two papers could impact the treatment of individuals with this devastating condition and perhaps other genetic eye diseases.
In the first paper, a team of researchers — led by Marius Ueffing, at the University of Tübingen, Germany, and Ronald Roepman, at Radboud University Nijmegen Medical Centre, The Netherlands — generated substantial new data regarding the mechanisms underlying LCA caused by mutations in the gene LCA5. Specifically, the team found that the protein templated by the LCA5 gene, Lebercillin, normally functions to control the movement of certain proteins within the cells in the eye that detect light (photoreceptors). When cells were engineered to express mutant Lebercillin templated by LCA-associated LCA5 mutations, Lebercillin was unable to interact with the transport machinery and proteins were no longer transported to their correct location in photoreceptors. This ultimately led to photoreceptor degeneration. Thus, the team was able to provide a molecular explanation of why certain genetic mutations lead to LCA.
Gene therapy has markedly improved the vision of several individuals with LCA caused by mutations in the gene RPE65. In the second paper, a team of researchers, led by Manzar Ashtari, at Children's Hospital of Philadelphia, Philadelphia, has now determined that the region of the brain that the treated eye provides information to is activated following the gene therapy despite having been deprived of sensory input for a very long time. This finding that the region of the brain that responds to visual imput can be reawakened after chronic sensory deprivation may have broader implications, suggesting that other eye diseases caused by retinal degeneration, both early- and late-onset, could perhaps be successfully treated with gene therapy.
TITLE: Disruption of intraflagellar protein transport in photoreceptor cilia causes Leber congenital amaurosis in humans and mice
AUTHOR CONTACT:
Marius Ueffing
Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
Phone: 49.7071.29.84021; Fax: 49.7071.29.4560; E-mail: marius.ueffing@uni-tuebingen.de.
Ronald Roepman
Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
Phone: 31.24.3610487; Fax: 31.24.3668752; E-mail: r.roepman@antrg.umcn.nl.
View this article at: http://www.jci.org/articles/view/45627?key=df29f902b905b58a3c3e
ACCOMPANYING ARTICLE
TITLE: The human visual cortex responds to gene therapy–mediated recovery of retinal function
AUTHOR CONTACT:
Manzar Ashtari
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Phone: 267.426.5690; Fax: 215.590.1345; E-mail: ashtari@email.chop.edu.
View this article at: http://www.jci.org/articles/view/57377?key=11cb5b78677699d463b4
ACCOMPANYING COMMENTARY
TITLE: Spotlight on childhood blindness
AUTHOR CONTACT:
José-Alain Sahel
Institut de la Vision, Pierre and Marie Curie Medical School-Paris, Paris, France.
Phone: 33153462504; Fax: 33140021499; E-mail: j-sahel@quinze-vingts.fr.
View this article at: http://www.jci.org/articles/view/58300?key=499c879fd0d290b927cd
TRANSPLANTATION: A breath of fresh air for lung transplant rejection
Only 50% of individuals who receive a lung transplant are alive 5 years after their transplant. This depressingly low percentage is largely a result of chronic rejection of the transplanted lung. Chronic rejection, which means repeated bouts of rejection symptoms beyond the first year after the transplant surgery, manifests as scarring to the small airways of the transplanted lung, a condition known as bronchiolitis obliterans syndrome (BOS). The mechanisms by which BOS develops remain largely undetermined, making the design of therapeutics difficult. However, a team of researchers, led by Mark Nicolls, at Stanford University School of Medicine, Stanford, has now generated data in an orthotopic tracheal transplantation system that lead them to suggest that developing approaches to enhance the integrity of blood vessels in a transplanted lung may promote graft health and prevent chronic rejection.
In an accompanying commentary, David Wilkes, at Indiana University School of Medicine, Indianapolis, provides a broad context for the work of Nicolls and colleagues and suggests that other nonimmune pathways underlying BOS will be discovered, providing yet more therapeutic targets.
TITLE: Adenovirus-mediated HIF-1-alpha gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection
AUTHOR CONTACT:
Mark R. Nicolls
VA Palo Alto Health Care System/Stanford University School of Medicine, Stanford, California, USA.
Phone: 650.493.5000, ext. 69289; Fax: 650.849.0553; E-mail: mnicolls@stanford.edu.
View this article at: http://www.jci.org/articles/view/46192?key=263983bce906ef60ac0e
ACCOMPANYING COMMENTARY
TITLE: Chronic lung allograft rejection and airway microvasculature: Is HIF-1 the missing link?
AUTHOR CONTACT:
David S. Wilkes
Indiana University School of Medicine, Indianapolis, Indiana, USA.
Phone: 317.278.7020; Fax 317.274.8439; E-mail: dwilkes@iupui.edu.
View this article at: http://www.jci.org/articles/view/58329?key=5914ac7c8feac666db57
VASCULAR BIOLOGY: Redefining the roles of the growth factor angiopoietin-1
Angiopoietin-1 is a growth factor that is critical for blood vessel development — mice lacking angiopoietin-1 die in utero as a result of blood vessel defects. It is also thought to be required to maintain mature blood vessels in a stable state. But now, a team of researchers, led by Susan Quaggin, at the University of Toronto, Toronto, has generated data in mice that redefine the roles of angiopoietin-1. The importance of these data is discussed in detail by Kari Alitalo and Pipsa Saharinen, at the University of Helsinki, in an accompanying commentary.
Using mice in which angiopoietin-1 could be deleted at different times during development (from conception to adulthood) and in different organs, Quaggin and colleagues confirmed that angiopoietin-1 is required for normal vascular development in the embryo, although they narrowed down the window of time in which it is required to between days 10.5 and 13.5 of gestation. Surprisingly, however, angiopoietin-1 was found to be dispensable in quiescent mature blood vessels. But, angiopoietin-1 deficiency resulted in profound organ damage, accelerated blood vessel growth, and fibrosis (scarring) in the context of tissue injury and microvascular disease in diabetes. Thus, while angiopoietin-1 is not required in quiescent mature blood vessels, it is an important modulator of the blood vessel response after injury, making it a potential therapeutic target for conditions associated with accelerated blood vessel growth and fibrosis.
TITLE: Angiopoietin-1 is essential in mouse vasculature during development and in response to injury
AUTHOR CONTACT:
Susan E. Quaggin
Mount Sinai Hospital, University of Toronto, Toronto, Canada.
Phone: 416.586.4800, ext. 2859; Fax: 416.586.5130; E-mail: quaggin@lunenfeld.ca.
View this article at: http://www.jci.org/articles/view/46322?key=9a693109229121e7bdd1
ACCOMPANYING COMMENTARY
TITLE: The yin, the yang, and the Angiopoietin-1
AUTHOR CONTACT:
Kari Alitalo
University of Helsinki, Helsinki, Finland.
Phone: 358.9.191.25511; Fax: 358.9.191.25510; E-mail: kari.alitalo@helsinki.fi.
View this article at: http://www.jci.org/articles/view/58196?key=b1a3f30b2540dec43f5a
METABOLIC DISEASE: Complicated control of food intake
Obesity is a major public health concern in developing countries because it increases an individual's risk of developing a large number of diseases including type 2 diabetes. Understanding the way in which the body tries to match food intake and energy expenditure over time could lead to new anti-obesity agents. New insight into such mechanisms is now provided by the work of Joel Elmquist and colleagues, at The University of Texas Southwestern Medical Center, Dallas, using genetically modified mice.
Leptin is one hormone that plays a role in matching food intake and energy expenditure over time. It is secreted by fat tissue and therefore its levels in the blood reflect overall fat mass. Leptin acts on nerve cells in several regions of the brain, via the protein Lepr, to decrease food intake and increase energy expenditure. However, its precise effects in different regions of the brain have not been determined. In new research, Elmquist and colleagues determined in mice that leptin acts on nerve cells that express the protein Glp-1 in a region of the brain known as the hindbrain to decrease food intake. Surprisingly, although mice lacking Lepr on these cells consumed abnormally large amounts of food, they didn't gain weight rapidly because energy expenditure by cells increased in response to the increased food intake. As noted by the authors and, in an accompanying commentary, Michael Schwartz, at the University of Washington, Seattle, the increased cellular energy expenditure observed in mice lacking Lepr on Glp-1–producing cells in the hindbrain was extremely unexpected because Lepr deletion in other regions of the brain results in decreased cellular energy expenditure. These suggest that the effects of leptin in the brain are more complicated than previously thought; it is vital to improve our understanding of this if we are to develop new anti-obesity approaches.
TITLE: Leptin receptor expression in hindbrain Glp-1 neurons regulates food intake and energy balance in mice
AUTHOR CONTACT:
Joel K. Elmquist
The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: 214.648.2911; Fax: 214.648.5044; E-mail: joel.elmquist@utsouthwestern.edu.
View this article at: http://www.jci.org/articles/view/43703?key=5909bbcd33964211a8e0
ACCOMPANYING COMMENTARY
TITLE: Neuroanatomy of body weight control: lessons learned from leptin
AUTHOR CONTACT:
Michael W. Schwartz
University of Washington, Seattle, Washington, USA.
Phone: 206.897.5288; Fax: 206.341.5293; E-mail: mschwart@u.washington.edu.
View this article at: http://www.jci.org/articles/view/58027?key=8c882a67f348c843a8d5
METABOLIC DISEASE: Taking out links in the signaling chain
In individuals who are obese, low blood levels of adiponectin, a hormone secreted from fat tissue, are associated with increased risk of developing conditions such as type 2 diabetes and coronary artery disease. Although the precise mechanisms by which adiponectin may antagonize the development of these conditions, adiponectin-mimetic therapies have become an attractive potential treatment. New insight into the molecular mechanisms by which adiponectin exerts its effects on the liver has now been provided by work performed using genetically modified mice by a team of researchers led by Morris Birnbaum, at the University of Pennsylvania, Philadelphia. Specifically, the team found that adiponectin controls liver cell expression of many genes involved in regulating glucose levels in the blood via a signaling pathway that does not involve the proteins LBK1 or AMPK, which were previously considered crucial mediators of this effect of adiponectin.
TITLE: Adiponectin suppresses gluconeogenic gene expression in mouse hepatocytes independent of LKB1-AMPK signaling
AUTHOR CONTACT:
Morris J. Birnbaum
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215.898.5001; Fax: 215.573.9138; E-mail: birnbaum@mail.med.upenn.edu.
View this article at: http://www.jci.org/articles/view/45942?key=650a6b7a7ed84ef7a757
Journal
Journal of Clinical Investigation