EDITOR'S PICK: The protein GRP78 opens the door to life-threatening fungal infection
Mucormycosis is a life-threatening infection most commonly caused by a species of fungus known as Rhizopus oryzae. It occurs predominantly in individuals with diabetes, in particular those with the potentially life-threatening complication known as diabetic ketoacidosis. A team of researchers, led by Ashraf Ibrahim, at the University of California Los Angeles, has now generated data in mice that provide an explanation as to why patients with DKA are highly susceptible to mucormyosis. The data also suggest a new avenue of research for those developing therapeutics for this life-threatening infection.
Mucormycosis is characterized by fungal invasion of the blood vessels, which results in blood clots forming in the blood vessels and local tissue destruction. In a series of in vitro experiments, the team identified the protein GRP78 as the protein to which Rhizopus oryzae binds on human blood vessel–lining cells. Interestingly, increased expression of GRP78 was observed on human blood vessel–lining cells cultured in levels of glucose and iron consistent with those seen during DKA and in the tissues that are affected during mucormycosis in mice with DKA, which are susceptible to the infection. Furthermore, mice with DKA were protected from murcomyosis by treatment with GRP78-specific immune serum. These data provide an explanation as to why patients with DKA are highly susceptible to mucormycosis and have uncovered a potential new approach to treating this life-threatening infection.
TITLE: The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice
AUTHOR CONTACT:
Ashraf S. Ibrahim
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
Phone: 310.222.6424; Fax: 310.782.2016; E-mail: ibrahim@labiomed.org.
View this article at: http://www.jci.org/articles/view/42164?key=847f8c223b15520428b3
EDITOR'S PICK: Noninvasively seeing a clear picture of immune cell function in vivo
Immune cell function in an individual can be monitored noninvasively in the clinic using a technique known as a PET scan. A team of researchers, led by Owen Witte, at the University of California, Los Angeles, has now determined that in mice two different PET probes used in the clinic to monitor immune cell function detect distinct immune cell populations. These data have implications for the interpretation of clinical PET scans performed with these two probes and suggest these probes could be used in the clinic to monitor the effects of drugs designed to target specific immune cell populations.
Immune cells use more glucose as their energy source when active. There are specific PET probes that can be used to detect this switch to increased glucose utilization. In this study, the researchers found that in mice with a retrovirus-induced sarcoma (a form of cancer that arises from connective tissue cells such as bone, cartilage, and fat cells) two PET probes that detect increased glucose utilization (FDG and FAC) accumulated in different immune cell populations. Specifically, FDG accumulated mainly in innate immune cells, while FAC accumulated predominantly in active CD8+ T cells. These data suggest that PET could be used more widely than it is currently to noninvasively evaluate the effectiveness of numerous immune modulating therapies.
TITLE: PET probes for distinct metabolic pathways have different cell specificities during immune responses in mice
AUTHOR CONTACT:
Owen N. Witte
University of California at Los Angeles, Los Angeles, California, USA.
Phone: 310.206.0386; Fax: 310.206.8822; E-mail: owenwitte@mednet.ucla.edu.
View this article at: http://www.jci.org/articles/view/41250?key=d8b807a4c80caaba59dd
DEVELOPMENT: A breath of vitamin A: the molecular link to lung formation
Evidence suggests that vitamin A deficiency is associated with lung birth defects. To understand the molecular mechanism for this effect it is important to understand exactly how vitamin A is involved in normal lung development from a structure in the embryo known as the primitive foregut. Insight into this has now been provided by research in mice performed by Wellington Cardoso and colleagues, at Boston University School of Medicine, Boston. Specifically, they found that vitamin A integrates two signaling pathways — the Wnt and TFG-beta pathways — to regulate levels of expression of the Fgf10 gene and induce the formation of the mouse primordial lung. The authors therefore suggest that vitamin A deficiency results in defective lung development is a result of disruption of Wnt/Tgfb/Fgf10 interactions.
TITLE: A retinoic acid–dependent network in the foregut controls formation of the mouse lung primordium
AUTHOR CONTACT:
Wellington V. Cardoso
Boston University School of Medicine, Boston, Massachusetts, USA.
Phone: 617.638.6198; Fax: 617.536.8093; E-mail: wcardoso@bu.edu.
View this article at: http://www.jci.org/articles/view/40253?key=ad36ad37ae16b0fa8cf2
IMMUNOLOGY: Context, context, context: all important for the immune function of NKT cells
A therapeutic approach to harnessing immune cells known as NKT cells, which have potent immunomodulatory properties, is currently being tested in cancer patients in phase I clinical trials. However, initial results suggest that the approach will need to be modified if clinical outcomes are to be maximized. Rational modification of the approach requires increased understanding of the molecules that regulate NKT cell activation in vivo. In this regard, Luc Teyton and colleagues, at The Scripps Research Institute, La Jolla, have identified the protein FAAH as a protein that modulates NKT cell responses in mice. Specifically they found that FAAH bound to the molecules that activate NKT cells and modulated the way in which they were presented to the NKT cells. Importantly, NKT cells responses in mice lacking FAAH differed from those in normal mice and were better at generating protective immunity in models of bacteria infection and tumor spread. These data suggest that modulating the context in which the molecules that activate NKT cells are found in the body could provide a way to enhance the effectiveness of vaccines.
TITLE: Fatty acid amide hydrolase shapes NKT cell responses by influencing the serum transport of lipid antigen in mice
AUTHOR CONTACT:
Luc Teyton
The Scripps Research Institute, La Jolla, California, USA.
Phone: 858.784.2728; Fax: 858.784.8166; E-mail: lteyton@scripps.edu.
View this article at: http://www.jci.org/articles/view/40451?key=434608950142c0b6882e
GASTROENTEROLOGY: Maintaining the barrier integrity of the gut
New research in mice, performed by Albert Reynolds and colleagues, at Vanderbilt University, Nashville, now suggests a role for the protein p120 in maintaining the integrity of the lining of the gut. These data are likely to have clinical relevance, as some studies have indicated that p120 is locally downregulated in many patients with inflammatory bowel disease (IBD).
IBD is a chronic, remitting inflammatory condition whose overall cause is poorly understood and multifactorial. Recent studies have indicated that adhesion molecules known as cadherins have a role in IBD. Consistent with the previous observation that the function of E-cadherin is regulated in part by p120, Reynolds and colleagues found that mice lacking p120 in the small intestine and colon died soon after birth as a result of massive intestinal bleeding caused by defects in adhesion between the cells lining the gut in both the small intestine and colon. An increase in inflammatory cells known as neutrophila in the tissue layer beneath the lining of the colon was also observed. These and other data presented in the study indicate that p120 deficiency in the mouse small intestine and colon leads to a loss of barrier integrity of the lining of the gut and increased neutrophil accumulation. The data also suggest a role for p120 in IBD.
TITLE: p120-catenin is essential for maintenance of barrier function and intestinal homeostasis in mice
AUTHOR CONTACT:
Albert B. Reynolds
Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Phone: 615.343.9532; Fax: 615.936.6399; E-mail: al.reynolds@vanderbilt.edu.
View this article at: http://www.jci.org/articles/view/41414?key=9650fa9139a9144cb265
HEMATOLOGY: The protein MCL1: a new therapeutic target in acute myeloid leukemia?
The approach to treating acute myeloid leukemia (AML) has not changed much over the past 30 years. Recent data suggest that targeting a group of proteins that inhibit cell death, the so called 'antiapoptotic BCL2 family members', might be a new approach to treating many forms of cancer. However, the functional significance and relative role of individual antiapoptotic BCL2 family members has not been determined. Through their analysis of leukemic cells from patients with AML and a mouse model of AML, a team of researchers, led by Michael Tomasson, at Washington University School of Medicine, St. Louis, has now determined that the antiapoptotic BCL2 family member MCL1 might make a good therapeutic target for the treatment of AML.
TITLE: Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia
AUTHOR CONTACT:
Michael H. Tomasson
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: 314.362.9350; Fax: 314.362.9333; E-mail: tomasson@wustl.edu.
View this article at: http://www.jci.org/articles/view/39964?key=f336c24cc2585d28cc0c
HEMATOLOGY: Tracking the spread of lymphomas with the protein p73
The protein p53 is well known to function as a suppressor of tumor development and progression. But whether its close relative p73 also does has not been unequivocally determined. Now, a team of researchers, led by Ute M. Moll, at Stony Brook University, Stony Brook, has found in a mouse model of B cell lymphoma that p73 does not suppress tumor formation but does repress widespread dissemination of the tumor. Consistent with the data generated in the mouse model of B cell lymphomas, p73 expression was observed to be frequently downregulated in human mature aggressive B cell lymphomas. Furthermore, both the incidence and degree of p73 downregulation in these tumors correlated with their dissemination status. The authors therefore suggest that assessing whether or not p73 has been downregulated in a B cell lymphoma could provide a way to identify those patients whose tumors are likely to have spread to distant sites.
TITLE: Loss of p73 promotes dissemination of Myc-induced B cell lymphomas in mice
AUTHOR CONTACT:
Ute M. Moll
Stony Brook University, Stony Brook, New York, USA.
Phone: 631.444.2459; Fax: 631.444.3424; E-mail: umoll@notes.cc.sunysb.edu.
View this article at: http://www.jci.org/articles/view/40331?key=49d97a29775def388ca0
CARDIOLOGY: Heart protection via sonic hedgehog
Erythropoietin (EPO) is a hormone that controls the production of red blood cells. In the clinic, administration of EPO provides tremendous benefit to individuals with congestive heart failure. The mechanisms underlying these effects of EPO have not been clearly determined. However, Issei Komuro and colleagues, at Chiba University Graduate School of Medicine, Japan, have now established that EPO prevents mouse heart muscle cells from dying and increases the number blood vessels in the hearts of mice after a heart attack. The beneficial effects of EPO were mediated via the signaling protein sonic hedgehog, providing a clear molecular explanation for the protection afforded to the heart by EPO administration.
TITLE: Sonic hedgehog is a critical mediator of erythropoietin-induced cardiac protection in mice
AUTHOR CONTACT:
Issei Komuro
Chiba University Graduate School of Medicine, Chiba, Japan.
Phone: 81.43.226.2097; Fax: 81.43.226.2557; E-mail: komuro-tky@umin.ac.jp.
View this article at: http://www.jci.org/articles/view/39896?key=a0dd9ec7a9e4226a7ea9
PULMONARY: Stopping the lung from scarring
Pulmonary fibrosis, a medical condition often described as scarring of the lungs, develops as a progressive, dysregulated response to lung injury. Disease progression results in dramatically impaired lung function and there are currently no good treatment options. However, a team of researchers, led by Paul Noble and Dianhua Jiang, at Duke University School of Medicine, Durham, has identified a potential new therapeutic approach to treating pulmonary fibrosis by studying a mouse model of the condition.
The team found that expression of the protein syndecan-4 increased in their mouse model and that pulmonary fibrosis was exacerbated in mice lacking syndecan-4. Further analysis indicated that syndecan-4 provided natural protection against pulmonary fibrosis by interacting with the protein CXCL10, a cellular attractant known to have anti-fibrotic properties. Importantly, a mutant CXCL10 protein incapable of mediating cellular attraction still protected mice in the model of pulmonary fibrosis in a syndecan-4–dependent manner. As the mutant CXCL10 protein incapable of mediating cellular attraction should have few side effects, unlike the normal protein, the authors suggest that it might provide a new therapy for the treatment of pulmonary fibrosis.
TITLE: Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4
AUTHOR CONTACT:
Paul W. Noble
Duke University School of Medicine, Durham, North Carolina, USA.
Phone: 919.681.0355; Fax: 919.684.5266; E-mail: paul.noble@duke.edu.
Dianhua Jiang
Duke University School of Medicine, Durham, North Carolina, USA.
Phone: 919.681.0355; Fax: 919.684.5266; E-mail: dianhua.jiang@duke.edu.
View this article at: http://www.jci.org/articles/view/38644?key=d79809117f6cb971bf4b
ENDOCRINOLOGY: Getting down to the specifics of GATA3 function in the parathyroid
Individuals with hypoparathyroidism–deafness–renal dysplasia (HDR) syndrome suffer from mild to profound hearing loss, some form of kidney disease, and hypoparathyroidism, a condition in which the function of the parathyroid gland is impaired, leading to low levels of calcium in the blood, a potentially life-threatening state. Although it is know that HDR is caused by mutations in the GATA3 gene, the function of GATA3 in parathyroid formation and function is not well known. However, a team of researchers, at the University of Oxford, United Kingdom, has now determined that GATA3 is critical for the generation and survival of parathyroid progenitor cells in mice. Further analysis indicated that the effects of GATA3 on parathyroid development and function are largely mediated via the protein Gcm2 (the equivalent of the human GCMB protein). The authors therefore suggest that hypoparathyroidism in individuals with HDR is caused by dysregulation of the GATA3/GCMB pathway.
TITLE: Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2
AUTHOR CONTACT:
Rajesh V. Thakker
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
Phone: 44.1865.857501; Fax: 44.1865.857502; E-mail: rajesh.thakker@ndm.ox.ac.uk.
View this article at: http://www.jci.org/articles/view/42021?key=d2ee7e09671f62db95b5
NEPHROLOGY: The protein NHE4 takes care handling acid in the kidney
A team of researchers, led by Pascal Houillier, at Hôpital Européen Georges Pompidou, France, has provided new insight into the regulation of acid levels in the body by studying in rodents the molecular mechanisms controlling the handling of ammonia by the kidney and its excretion in the urine.
Ammonia is the main acid component of urine. Transport of ammonia out of cells in the kidney known as MTALH cells and the subsequent excretion of ammonia in the urine is critical for regulating acid levels in the body. In the study, analysis of mice lacking the transport protein NHE4 and of NHE4 activity in the rat kidney indicated that NHE4 is important for ammonia transport by MTALH cells and maintenance of normal acid-base balance in the body. The authors therefore conclude that NHE4 could be at fault in individuals with adult renal tubular acidosis, a medical condition characterized by the accumulation of acid in the body due to a failure of the kidneys to remove acid from the body in the urine.
TITLE: NHE4 is critical for the renal handling of ammonia in rodents
AUTHOR CONTACT:
Pascal Houillier
Hôpital Européen Georges Pompidou, Paris, France.
Phone: 33.1.56.09.39.72; Fax: 33.1.56.09.26.75; E-mail: pascal.houillier@egp.aphp.fr.
View this article at: http://www.jci.org/articles/view/36581?key=94570b9268b7f9b98f61
Journal
Journal of Clinical Investigation