There have been exciting recent advances in our understanding of the structural and molecular biology of the glomerular slit diaphragm, as described in a report in this issue of the JCI. These findings, combined with data on the permeability of the basement membrane and evidence that the endothelium may be a more important barrier than often supposed, are allowing a clearer understanding to emerge of how the 3 parts of the glomerular capillary wall jointly determine its functional properties.
William M. Deen
The Randle cycle, which has been invoked to explain the reciprocal relationship between fatty acid oxidation and glucose oxidation, has long been implicated as a potential mechanism for hyperglycemia and type 2 diabetes mellitus (T2DM). Now genetic, functional genomic, and transgenic approaches have identified PPARγ coactivators (PGC-1α and PGC-1β) as key regulators of mitochondrial number and function. They regulate adaptive thermogenesis as well as glucose and fat oxidation in muscle and fat tissue, gluconeogenesis in liver, and even glucose-regulated insulin secretion in β cells. PGC-1α and PGC-1β mRNA levels and the mitochondrial genes they regulate are decreased in muscle of people with prediabetes and T2DM. A new report indicates that PGC-1α and PGC-1β mRNA levels decrease with age in individuals with a genetic variant in PGC-1α, and these decreases correlate with alterations in whole-body glucose and fatty acid oxidation. These findings provide insights into how aging modifies genetic susceptibility to alterations in oxidative phosphorylation and T2DM.
Alan R. Shuldiner, John C. McLenithan
Kinase suppressor of Ras-1 (KSR1) is a recently identified member of the EGFR–Ras–Raf-1–MAPK signaling pathway. A new study demonstrates that KSR1 protects intestinal epithelium from TNF-α–induced apoptosis, abrogating inflammatory bowel disease (IBD). Since its discovery, there has been disagreement as to whether KSR1 possesses intrinsic kinase activity. Using transgenic mouse models and genetically modified mouse colon epithelial cells, Polk and coworkers show that the kinase activity of KSR1 is off in normal colon epithelial cells, becoming activated only at the onset of IBD. They also provide strong evidence that KSR1 kinase activity is essential for anti-apoptotic protection of the intestinal epithelium. These new data in support of KSR1 as a kinase highlight an ongoing debate as to whether KSR1 does indeed serve as a specific kinase in transphosphorylating and transactivating c-Raf–1 toward MEK1.
Richard Kolesnick, H. Rosie Xing
Cellular senescence induced by different stresses and telomere shortening appears to play an important role in the aging process. The products of the INK4a/ARF locus — p16INK4a and ARF — arrest cell proliferation at the senescence stage by exerting their effects on retinoblastoma protein– and p53-mediated responsive pathways. A study in this issue of the JCI provides experimental evidence of a specific upregulation of these cell cycle inhibitors in a variety of organs during mammalian aging.
Ande Satyanarayana, K. Lenhard Rudolph
DNA vaccination is a novel immunization strategy that has great potential for the development of vaccines and immune therapeutics. This strategy has been highly effective in mice, while less immunogenic in nonhuman primates and humans. Enhancing DNA vaccine potency remains a challenge. It is likely that APCs, and especially DCs, play a paramount role in the presentation of vaccine antigen to the immune system. A new study reports the synergistic recruitment, expansion, and activation of DCs in vivo in a mouse model through covaccination with plasmids encoding macrophage inflammatory protein-1α (MIP-1α), fms-like tyrosine kinase 3 ligand (Flt3L), and the DNA vaccine. Such cooperative strategies delivering vaccine in a single, simple platform result in improved cellular immunity in vivo, including enhanced tetramer responses and IFN-γ secretion by antigen-specific cells.
Michele A. Kutzler, David B. Weiner
HDL has a key role in reverse cholesterol transport, mobilizing cholesterol from the peripheral tissues to liver. In this process, the ABC transporter A1 (ABCA1) protein controls the efflux of intracellular cholesterol to apoAI, the major apolipoprotein of HDL. Since ABCA1 mutations were discovered to cause Tangier disease, a rare recessive HDL deficiency, it has been speculated that sequence variants in ABCA1 might also contribute to variations in plasma HDL cholesterol levels in the general population. A new study provides genetic evidence supporting this hypothesis.
Päivi Pajukanta
Angiogenesis is regulated in large part by the balance of various proangiogenic stimulators, such as VEGF, and a diverse group of endogenous inhibitors of angiogenesis, most of which are extrinsic to endothelial cells. With respect to the latter, until recently, none have appeared to be induced as a consequence of a specific, self-regulating, feedback inhibition response. A new inhibitor, called vasohibin, has been uncovered. Vasohibin is selectively induced in endothelial cells by proangiogenic stimulatory growth factors such as VEGF; it appears to operate as an intrinsic and highly specific feedback inhibitor of activated endothelial cells engaged in the process of angiogenesis.
Robert S. Kerbel
The etiology of type 2 diabetes is characterized by obesity, insulin and leptin resistance, and compensatory β cell hyperplasia followed by islet degeneration, resulting in the eventual dysregulation of glucose and lipid homeostasis. The recent identification of insulin receptor substrate 2 (IRS2) as a central player in the pathophysiology of many of these processes suggests a potentially unifying molecular link underlying the initiation and progression of type 2 diabetes.
Matthew J. Brady
Hemoglobinopathies are caused by abnormal structure or synthesis of hemoglobin chains and represent serious monogenic disorders. A new study demonstrates that lentiviral vectors can express clinically relevant levels of human transgenic β-globin in red cells of xenografted mice. While some safety concerns must be addressed, this study is an important step toward potential clinical trials of gene therapy for hemoglobinopathies.
Christof von Kalle, Christopher Baum, David A. Williams
It has been difficult to develop therapies that target those T cells initiating and mediating the pathogenesis of autoimmune disease. Indeed, most current treatments indiscriminately affect both the autoreactive T cells and the “good” T cells, putting the patient at risk of compromised immune function. A new approach raises the possibility of targeted therapy for autoimmunity. Transplantation of hematopoietic stem cells modified to express a protective form of MHC class II corrects a defect in central tolerance. This method contrasts with other targeted therapies that attempt to modify peripheral tolerance, which is also defective in type 1 diabetes mellitus.
Rémi J. Creusot, C. Garrison Fathman
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