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Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy. For the childhood cancer neuroblastoma, amplification of the oncogene MYCN is associated with high-risk disease and poor prognosis. Here, we deployed genome-scale CRISPR-Cas9 screening of MYCN-amplified neuroblastoma and found a preferential dependency on genes encoding the polycomb repressive complex 2 (PRC2) components EZH2, EED, and SUZ12. Genetic and pharmacological suppression of EZH2 inhibited neuroblastoma growth in vitro and in vivo. Moreover, compared with neuroblastomas without MYCN amplification, MYCN-amplified neuroblastomas expressed higher levels of EZH2. ChIP analysis showed that MYCN binds at the EZH2 promoter, thereby directly driving expression. Transcriptomic and epigenetic analysis, as well as genetic rescue experiments, revealed that EZH2 represses neuronal differentiation in neuroblastoma in a PRC2-dependent manner. Moreover, MYCN-amplified and high-risk primary tumors from patients with neuroblastoma exhibited strong repression of EZH2-regulated genes. Additionally, overexpression of IGFBP3, a direct EZH2 target, suppressed neuroblastoma growth in vitro and in vivo. We further observed strong synergy between histone deacetylase inhibitors and EZH2 inhibitors. Together, these observations demonstrate that MYCN upregulates EZH2, leading to inactivation of a tumor suppressor program in neuroblastoma, and support testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma.
Liying Chen, Gabriela Alexe, Neekesh V. Dharia, Linda Ross, Amanda Balboni Iniguez, Amy Saur Conway, Emily Jue Wang, Veronica Veschi, Norris Lam, Jun Qi, W. Clay Gustafson, Nicole Nasholm, Francisca Vazquez, Barbara A. Weir, Glenn S. Cowley, Levi D. Ali, Sasha Pantel, Guozhi Jiang, William F. Harrington, Yenarae Lee, Amy Goodale, Rakela Lubonja, John M. Krill-Burger, Robin M. Meyers, Aviad Tsherniak, David E. Root, James E. Bradner, Todd R. Golub, Charles W.M. Roberts, William C. Hahn, William A. Weiss, Carol J. Thiele, Kimberly Stegmaier
Total views: 2767
Nervous system injury is a frequent result of cancer therapy involving cranial irradiation, leaving patients with marked memory and other neurobehavioral disabilities. Here, we report an unanticipated link between bone marrow and brain in the setting of radiation injury. Specifically, we demonstrate that bone marrow–derived monocytes and macrophages are essential for structural and functional repair mechanisms, including regeneration of cerebral white matter and improvement in neurocognitive function. Using a granulocyte-colony stimulating factor (G-CSF) receptor knockout mouse model in combination with bone marrow cell transplantation, MRI, and neurocognitive functional assessments, we demonstrate that bone marrow–derived G-CSF–responsive cells home to the injured brain and are critical for altering neural progenitor cells and brain repair. Additionally, compared with untreated animals, animals that received G-CSF following radiation injury exhibited enhanced functional brain repair. Together, these results demonstrate that, in addition to its known role in defense and debris removal, the hematopoietic system provides critical regenerative drive to the brain that can be modulated by clinically available agents.
Jorg Dietrich, Ninib Baryawno, Naema Nayyar, Yannis K. Valtis, Betty Yang, Ina Ly, Antoine Besnard, Nicolas Severe, Karin U. Gustafsson, Ovidiu C. Andronesi, Tracy T. Batchelor, Amar Sahay, David T. Scadden
Total views: 2612
Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by duplication of peripheral myelin protein 22 (PMP22) and is the most common hereditary peripheral neuropathy. CMT1A is characterized by demyelination and axonal loss, which underlie slowed motor nerve conduction velocity (MNCV) and reduced compound muscle action potentials (CMAP) in patients. There is currently no known treatment for this disease. Here, we show that antisense oligonucleotides (ASOs) effectively suppress PMP22 mRNA in affected nerves in 2 murine CMT1A models. Notably, initiation of ASO treatment after disease onset restored myelination, MNCV, and CMAP almost to levels seen in WT animals. In addition to disease-associated gene expression networks that were restored with ASO treatment, we also identified potential disease biomarkers through transcriptomic profiling. Furthermore, we demonstrated that reduction of PMP22 mRNA in skin biopsies from ASO-treated rats is a suitable biomarker for evaluating target engagement in response to ASO therapy. These results support the use of ASOs as a potential treatment for CMT1A and elucidate potential disease and target engagement biomarkers for use in future clinical trials.
Hien Tran Zhao, Sagar Damle, Karli Ikeda-Lee, Steven Kuntz, Jian Li, Apoorva Mohan, Aneeza Kim, Gene Hung, Mark A. Scheideler, Steven S. Scherer, John Svaren, Eric E. Swayze, Holly B. Kordasiewicz
Total views: 2353
Type 2 diabetes mellitus (T2DM) is a common complication of obesity. Here, we have shown that activation of the IgG receptor FcγRIIB in endothelium by hyposialylated IgG plays an important role in obesity-induced insulin resistance. Despite becoming obese on a high-fat diet (HFD), mice lacking FcγRIIB globally or selectively in endothelium were protected from insulin resistance as a result of the preservation of insulin delivery to skeletal muscle and resulting maintenance of muscle glucose disposal. IgG transfer in IgG-deficient mice implicated IgG as the pathogenetic ligand for endothelial FcγRIIB in obesity-induced insulin resistance. Moreover, IgG transferred from patients with T2DM but not from metabolically healthy subjects caused insulin resistance in IgG-deficient mice via FcγRIIB, indicating that similar processes may be operative in T2DM in humans. Mechanistically, the activation of FcγRIIB by IgG from obese mice impaired endothelial cell insulin transcytosis in culture and in vivo. These effects were attributed to hyposialylation of the Fc glycan, and IgG from T2DM patients was also hyposialylated. In HFD-fed mice, supplementation with the sialic acid precursor N-acetyl-D-mannosamine restored IgG sialylation and preserved insulin sensitivity without affecting weight gain. Thus, IgG sialylation and endothelial FcγRIIB may represent promising therapeutic targets to sever the link between obesity and T2DM.
Keiji Tanigaki, Anastasia Sacharidou, Jun Peng, Ken L. Chambliss, Ivan S. Yuhanna, Debabrata Ghosh, Mohamed Ahmed, Alexander J. Szalai, Wanpen Vongpatanasin, Robert F. Mattrey, Qiushi Chen, Parastoo Azadi, Ildiko Lingvay, Marina Botto, William L. Holland, Jennifer J. Kohler, Shashank R. Sirsi, Kenneth Hoyt, Philip W. Shaul, Chieko Mineo
Total views: 2192
During tumor progression, immune system phagocytes continually clear apoptotic cancer cells in a process known as efferocytosis. However, the impact of efferocytosis in metastatic tumor growth is unknown. In this study, we observed that macrophage-driven efferocytosis of prostate cancer cells in vitro induced the expression of proinflammatory cytokines such as CXCL5 by activating Stat3 and NF-κB(p65) signaling. Administration of a dimerizer ligand (AP20187) triggered apoptosis in 2 in vivo syngeneic models of bone tumor growth in which apoptosis-inducible prostate cancer cells were either coimplanted with vertebral bodies, or inoculated in the tibiae of immunocompetent mice. Induction of 2 pulses of apoptosis correlated with increased infiltration of inflammatory cells and accelerated tumor growth in the bone. Apoptosis-induced tumors displayed elevated expression of the proinflammatory cytokine CXCL5. Likewise, CXCL5-deficient mice had reduced tumor progression. Peripheral blood monocytes isolated from patients with bone metastasis of prostate cancer were more efferocytic compared with normal controls, and CXCL5 serum levels were higher in metastatic prostate cancer patients relative to patients with localized prostate cancer or controls. Altogether, these findings suggest that the myeloid phagocytic clearance of apoptotic cancer cells accelerates CXCL5-mediated inflammation and tumor growth in bone, pointing to CXCL5 as a potential target for cancer therapeutics.
Hernan Roca, Jacqueline D. Jones, Marta C. Purica, Savannah Weidner, Amy J. Koh, Robert Kuo, John E. Wilkinson, Yugang Wang, Stephanie Daignault-Newton, Kenneth J. Pienta, Todd M. Morgan, Evan T. Keller, Jacques E. Nör, Lonnie D. Shea, Laurie K. McCauley
Total views: 2171
Synovial sarcoma (SS) is an aggressive soft-tissue sarcoma that is often discovered during adolescence and young adulthood. Despite the name, synovial sarcoma does not typically arise from a synoviocyte but instead arises in close proximity to bones. Previous work demonstrated that mice expressing the characteristic SS18-SSX fusion oncogene in myogenic factor 5–expressing (Myf5-expressing) cells develop fully penetrant sarcomagenesis, suggesting skeletal muscle progenitor cell origin. However, Myf5 is not restricted to committed myoblasts in embryos but is also expressed in multipotent mesenchymal progenitors. Here, we demonstrated that human SS and mouse tumors arising from SS18-SSX expression in the embryonic, but not postnatal, Myf5 lineage share an anatomic location that is frequently adjacent to bone. Additionally, we showed that SS can originate from periosteal cells expressing SS18-SSX alone and from preosteoblasts expressing the fusion oncogene accompanied by the added stabilization of β-catenin, which is a common secondary change in SS. Expression and secretion of the osteoclastogenesis inhibitory factor osteoprotegerin enabled early growth of SS18-SSX2–transformed cells, indicating a paracrine link between the bone and synovial sarcomagenesis. These findings explain the skeletal contact frequently observed in human SS and may provide alternate means of enabling SS18-SSX–driven oncogenesis in cells as differentiated as preosteoblasts.
Jared J. Barrott, Benjamin E. Illum, Huifeng Jin, Matthew L. Hedberg, Yanliang Wang, Allie Grossmann, Malay Haldar, Mario R. Capecchi, Kevin B. Jones
Total views: 1991
Metabolic reprogramming in breast tumors is linked to increases in putative oncogenic metabolites that may contribute to malignant transformation. We previously showed that accumulation of the oncometabolite, 2-hydroxyglutarate (2HG), in breast tumors was associated with MYC signaling, but not with isocitrate dehydrogenase (IDH) mutations, suggesting a distinct mechanism for increased 2HG in breast cancer. Here, we determined that D-2HG is the predominant enantiomer in human breast tumors and show that the D-2HG–producing mitochondrial enzyme, alcohol dehydrogenase, iron-containing protein 1 (ADHFE1), is a breast cancer oncogene that decreases patient survival. We found that MYC upregulates ADHFE1 through changes in iron metabolism while coexpression of both ADHFE1 and MYC strongly enhanced orthotopic tumor growth in MCF7 cells. Moreover, ADHFE1 promoted metabolic reprogramming with increased formation of D-2HG and reactive oxygen, a reductive glutamine metabolism, and modifications of the epigenetic landscape, leading to cellular dedifferentiation, enhanced mesenchymal transition, and phenocopying alterations that occur with high D-2HG levels in cancer cells with IDH mutations. Together, our data support the hypothesis that ADHFE1 and MYC signaling contribute to D-2HG accumulation in breast tumors and show that D-2HG is an oncogenic metabolite and potential driver of disease progression.
Prachi Mishra, Wei Tang, Vasanta Putluri, Tiffany H. Dorsey, Feng Jin, Fang Wang, Donewei Zhu, Lauren Amable, Tao Deng, Shaofei Zhang, J. Keith Killian, Yonghong Wang, Tsion Z. Minas, Harry G. Yfantis, Dong H. Lee, Arun Sreekumar, Michael Bustin, Wei Liu, Nagireddy Putluri, Stefan Ambs
Total views: 1966
Obesity is a principal causative factor in the development of metabolic syndrome. Here we report that increased oxidative stress in accumulated fat is an important pathogenic mechanism of obesity-associated metabolic syndrome. Fat accumulation correlated with systemic oxidative stress in humans and mice. Production of ROS increased selectively in adipose tissue of obese mice, accompanied by augmented expression of NADPH oxidase and decreased expression of antioxidative enzymes. In cultured adipocytes, elevated levels of fatty acids increased oxidative stress via NADPH oxidase activation, and oxidative stress caused dysregulated production of adipocytokines (fat-derived hormones), including adiponectin, plasminogen activator inhibitor–1, IL-6, and monocyte chemotactic protein–1. Finally, in obese mice, treatment with NADPH oxidase inhibitor reduced ROS production in adipose tissue, attenuated the dysregulation of adipocytokines, and improved diabetes, hyperlipidemia, and hepatic steatosis. Collectively, our results suggest that increased oxidative stress in accumulated fat is an early instigator of metabolic syndrome and that the redox state in adipose tissue is a potentially useful therapeutic target for obesity-associated metabolic syndrome.
Shigetada Furukawa, Takuya Fujita, Michio Shimabukuro, Masanori Iwaki, Yukio Yamada, Yoshimitsu Nakajima, Osamu Nakayama, Makoto Makishima, Morihiro Matsuda, Iichiro Shimomura
Total views: 1801
As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non–BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.
Sascha Dietrich, Małgorzata Oleś, Junyan Lu, Leopold Sellner, Simon Anders, Britta Velten, Bian Wu, Jennifer Hüllein, Michelle da Silva Liberio, Tatjana Walther, Lena Wagner, Sophie Rabe, Sonja Ghidelli-Disse, Marcus Bantscheff, Andrzej K. Oleś, Mikołaj Słabicki, Andreas Mock, Christopher C. Oakes, Shihui Wang, Sina Oppermann, Marina Lukas, Vladislav Kim, Martin Sill, Axel Benner, Anna Jauch, Lesley Ann Sutton, Emma Young, Richard Rosenquist, Xiyang Liu, Alexander Jethwa, Kwang Seok Lee, Joe Lewis, Kerstin Putzker, Christoph Lutz, Davide Rossi, Andriy Mokhir, Thomas Oellerich, Katja Zirlik, Marco Herling, Florence Nguyen-Khac, Christoph Plass, Emma Andersson, Satu Mustjoki, Christof von Kalle, Anthony D. Ho, Manfred Hensel, Jan Dürig, Ingo Ringshausen, Marc Zapatka, Wolfgang Huber, Thorsten Zenz
Total views: 1699
Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and triglyceride synthesis but was associated with improved hepatic insulin signaling. Metabolomic and RNA sequence analysis confirmed dichotomous effects of fructose and glucose supplementation on liver metabolism in spite of inducing similar hepatic lipid accumulation. Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese humans with steatohepatitis. Knockdown of ketohexokinase in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice. Thus, fructose is a component of dietary sugar that is distinctively associated with poor metabolic outcomes, whereas increased glucose intake may be protective.
Samir Softic, Manoj K. Gupta, Guo-Xiao Wang, Shiho Fujisaka, Brian T. O’Neill, Tata Nageswara Rao, Jennifer Willoughby, Carole Harbison, Kevin Fitzgerald, Olga Ilkayeva, Christopher B. Newgard, David E. Cohen, C. Ronald Kahn
Total views: 1631
Microglia are brain-resident myeloid cells that mediate key functions to support the CNS. Microglia express a wide range of receptors that act as molecular sensors, which recognize exogenous or endogenous CNS insults and initiate an immune response. In addition to their classical immune cell function, microglia act as guardians of the brain by promoting phagocytic clearance and providing trophic support to ensure tissue repair and maintain cerebral homeostasis. Conditions associated with loss of homeostasis or tissue changes induce several dynamic microglial processes, including changes of cellular morphology, surface phenotype, secretory mediators, and proliferative responses (referred to as an “activated state”). Activated microglia represent a common pathological feature of several neurodegenerative diseases, including Alzheimer’s disease (AD). Cumulative evidence suggests that microglial inflammatory activity in AD is increased while microglial-mediated clearance mechanisms are compromised. Microglia are perpetually engaged in a mutual interaction with the surrounding environment in CNS; thus, diverse microglial reactions at different disease stages may open new avenues for therapeutic intervention and modification of inflammatory activities. In this Review, the role of microglia in the pathogenesis of AD and the modulation of microglia activity as a therapeutic modality will be discussed.
Heela Sarlus, Michael T. Heneka
Total views: 769
Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges to the peripheral (CNS-draining) lymph nodes. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems.
Antoine Louveau, Benjamin A. Plog, Salli Antila, Kari Alitalo, Maiken Nedergaard, Jonathan Kipnis
Total views: 729
There are currently over 1.9 billion people who are obese or overweight, leading to a rise in related health complications, including insulin resistance, type 2 diabetes, cardiovascular disease, liver disease, cancer, and neurodegeneration. The finding that obesity and metabolic disorder are accompanied by chronic low-grade inflammation has fundamentally changed our view of the underlying causes and progression of obesity and metabolic syndrome. We now know that an inflammatory program is activated early in adipose expansion and during chronic obesity, permanently skewing the immune system to a proinflammatory phenotype, and we are beginning to delineate the reciprocal influence of obesity and inflammation. Reviews in this series examine the activation of the innate and adaptive immune system in obesity; inflammation within diabetic islets, brain, liver, gut, and muscle; the role of inflammation in fibrosis and angiogenesis; the factors that contribute to the initiation of inflammation; and therapeutic approaches to modulate inflammation in the context of obesity and metabolic syndrome.
Alan R. Saltiel, Jerrold M. Olefsky
Total views: 517
Type 1 diabetes (T1D) is a chronic autoimmune disease that causes severe loss of pancreatic β cells. Autoreactive T cells are key mediators of β cell destruction. Studies of organ donors with T1D that have examined T cells in pancreas, the diabetogenic insulitis lesion, and lymphoid tissues have revealed a broad repertoire of target antigens and T cell receptor (TCR) usage, with initial evidence of public TCR sequences that are shared by individuals with T1D. Neoepitopes derived from post-translational modifications of native antigens are emerging as novel targets that are more likely to evade self-tolerance. Further studies will determine whether T cell responses to neoepitopes are major disease drivers that could impact prediction, prevention, and therapy. This Review provides an overview of recent progress in our knowledge of autoreactive T cells that has emerged from experimental and clinical research as well as pathology investigations.
Total views: 474
There is an increasing recognition that inflammation plays a critical role in neurodegenerative diseases of the CNS, including Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and the prototypic neuroinflammatory disease multiple sclerosis (MS). Differential immune responses involving the adaptive versus the innate immune system are observed at various stages of neurodegenerative diseases, and may not only drive disease processes but could serve as therapeutic targets. Ongoing investigations into the specific inflammatory mechanisms that play roles in disease causation and progression have revealed lessons about inflammation-driven neurodegeneration that can be applied to other neurodegenerative diseases. An increasing number of immunotherapeutic strategies that have been successful in MS are now being applied to other neurodegenerative diseases. Some approaches suppress CNS immune mechanisms, while others harness the immune system to clear deleterious products and cells. This Review focuses on the mechanisms by which inflammation, mediated either by the peripheral immune response or by endogenous CNS immune mechanisms, can affect CNS neurodegeneration.
Tanuja Chitnis, Howard L. Weiner
Total views: 451
A major subset of human cancers shows evidence for spontaneous adaptive immunity, which is reflected by the presence of infiltrating CD8+ T cells specific for tumor antigens within the tumor microenvironment. This observation has raised the question of which innate immune sensing pathway might detect the presence of cancer and lead to a natural adaptive antitumor immune response in the absence of exogenous infectious pathogens. Evidence for a critical functional role for type I IFNs led to interrogation of candidate innate immune sensing pathways that might be triggered by tumor presence and induce type I IFN production. Such analyses have revealed a major role for the stimulator of IFN genes pathway (STING pathway), which senses cytosolic tumor–derived DNA within the cytosol of tumor-infiltrating DCs. Activation of this pathway is correlated with IFN-β production and induction of antitumor T cells. Based on the biology of this natural immune response, pharmacologic agonists of the STING pathway are being developed to augment and optimize STING activation as a cancer therapy. Intratumoral administration of STING agonists results in remarkable therapeutic activity in mouse models, and STING agonists are being carried forward into phase I clinical testing.
Leticia Corrales, Sarah M. McWhirter, Thomas W. Dubensky Jr., Thomas F. Gajewski
Total views: 432
An understanding of the events that initiate metabolic inflammation (metainflammation) can support the identification of targets for preventing metabolic disease and its negative effects on health. There is ample evidence demonstrating that the initiating events in obesity-induced inflammation start early in childhood. This has significant implications on our understanding of how early life events in childhood influence adult disease. In this Review we frame the initiating events of metainflammation in the context of child development and discuss what this reveals about the mechanisms by which this unique form of chronic inflammation is initiated and sustained into adulthood.
Kanakadurga Singer, Carey N. Lumeng
Total views: 357
Amyotrophic lateral sclerosis (ALS) is a degenerative disorder that is characterized by loss of motor neurons and shows clinical, pathological, and genetic overlap with frontotemporal dementia (FTD). Activated microglia are a universal feature of ALS/FTD pathology; however, their role in disease pathogenesis remains incompletely understood. The recent discovery that ORF 72 on chromosome 9 (C9orf72), the gene most commonly mutated in ALS/FTD, has an important role in myeloid cells opened the possibility that altered microglial function plays an active role in disease. This Review highlights the contribution of microglia to ALS/FTD pathogenesis, discusses the connection between autoimmunity and ALS/FTD, and explores the possibility that C9orf72 and other ALS/FTD genes may have a “dual effect” on both neuronal and myeloid cell function that could explain a shared propensity for altered systemic immunity and neurodegeneration.
Deepti Lall, Robert H. Baloh
Total views: 313
Spinal cord injury (SCI) lesions present diverse challenges for repair strategies. Anatomically complete injuries require restoration of neural connectivity across lesions. Anatomically incomplete injuries may benefit from augmentation of spontaneous circuit reorganization. Here, we review SCI cell biology, which varies considerably across three different lesion-related tissue compartments: (a) non-neural lesion core, (b) astrocyte scar border, and (c) surrounding spared but reactive neural tissue. After SCI, axon growth and circuit reorganization are determined by neuron-cell-autonomous mechanisms and by interactions among neurons, glia, and immune and other cells. These interactions are shaped by both the presence and the absence of growth-modulating molecules, which vary markedly in different lesion compartments. The emerging understanding of how SCI cell biology differs across lesion compartments is fundamental to developing rationally targeted repair strategies.
Timothy M. O’Shea, Joshua E. Burda, Michael V. Sofroniew
Total views: 289
Many RNA species have been identified as important players in the development of chronic diseases, including cancer. Over the past decade, numerous studies have highlighted how regulatory RNAs such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) play crucial roles in the development of a disease state. It is clear that the aberrant expression of miRNAs promotes tumor initiation and progression, is linked with cardiac dysfunction, allows for the improper physiological response in maintaining glucose and insulin levels, and can prevent the appropriate integration of neuronal networks, resulting in neurodegenerative disorders. Because of this, there has been a major effort to therapeutically target these noncoding RNAs. In just the past 5 years, over 100 antisense oligonucleotide–based therapies have been tested in phase I clinical trials, a quarter of which have reached phase II/III. Most notable are fomivirsen and mipomersen, which have received FDA approval to treat cytomegalovirus retinitis and high blood cholesterol, respectively. The continued improvement of innovative RNA modifications and delivery entities, such as nanoparticles, will aid in the development of future RNA-based therapeutics for a broader range of chronic diseases. Here we summarize the latest promises and challenges of targeting noncoding RNAs in disease.
Brian D. Adams, Christine Parsons, Lisa Walker, Wen Cai Zhang, Frank J. Slack
Total views: 274