Teresa Muñoz-Galdeano

Bio: Teresa Muñoz-Galdeano is an academic researcher from Spanish National Research Council. The author has contributed to research in topics: microRNA & Spinal cord injury. The author has an hindex of 6, co-authored 10 publications receiving 268 citations.

MicroRNA Dysregulation in the Spinal Cord following Traumatic Injury

Abstract: Spinal cord injury (SCI) triggers a multitude of pathophysiological events that are tightly regulated by the expression levels of specific genes. Recent studies suggest that changes in gene expression following neural injury can result from the dysregulation of microRNAs, short non-coding RNA molecules that repress the translation of target mRNA. To understand the mechanisms underlying gene alterations following SCI, we analyzed the microRNA expression patterns at different time points following rat spinal cord injury. The microarray data reveal the induction of a specific microRNA expression pattern following moderate contusive SCI that is characterized by a marked increase in the number of down-regulated microRNAs, especially at 7 days after injury. MicroRNA downregulation is paralleled by mRNA upregulation, strongly suggesting that microRNAs regulate transcriptional changes following injury. Bioinformatic analyses indicate that changes in microRNA expression affect key processes in SCI physiopathology, including inflammation and apoptosis. MicroRNA expression changes appear to be influenced by an invasion of immune cells at the injury area and, more importantly, by changes in microRNA expression specific to spinal cord cells. Comparisons with previous data suggest that although microRNA expression patterns in the spinal cord are broadly similar among vertebrates, the results of studies assessing SCI are much less congruent and may depend on injury severity. The results of the present study demonstrate that moderate spinal cord injury induces an extended microRNA downregulation paralleled by an increase in mRNA expression that affects key processes in the pathophysiology of this injury.

MicroRNA dysregulation in spinal cord injury: causes, consequences and therapeutics.

Abstract: Trauma to the spinal cord causes permanent disability to more than 180,000 people every year worldwide. The initial mechanical damage triggers a complex set of secondary events involving the neural, vascular, and immune systems that largely determine the functional outcome of the spinal cord injury (SCI). Cellular and biochemical mechanisms responsible for this secondary injury largely depend on activation and inactivation of specific gene programs. Recent studies indicate that microRNAs function as gene expression switches in key processes of the SCI. Microarray data from rodent contusion models reveal that SCI induces changes in the global microRNA expression patterns. Variations in microRNA abundance largely result from alterations in the expression of the cells at the damaged spinal cord. However, microRNA expression levels after SCI are also influenced by the infiltration of immune cells to the injury site and the death and migration of specific neural cells after injury. Evidences on the role of microRNAs in the SCI pathophysiology have come from different sources. Bioinformatic analysis of microarray data has been used to identify specific variations in microRNA expression underlying transcriptional changes in target genes, which are involved in key processes in the SCI. Direct evidences on the role of microRNAs in SCI are scarcer, although recent studies have identified several microRNAs (miR-21, miR-486, miR-20) involved in key mechanisms of the SCI such as cell death or astrogliosis, among others. From a clinical perspective, different evidences make clear that microRNAs can be potent therapeutic tools to manipulate cell state and molecular processes in order to enhance functional recovery. The present article reviews the actual knowledge on how injury affects microRNA expression and the meaning of these changes in the SCI pathophysiology, to finally explore the clinical potential of microRNAs in the SCI.

Deer antler innervation and regeneration.

Abstract: Nervous system injuries are a major cause of impairment in the human society. Up to now, clinical approaches have failed to adequately restore function following nervous system damage. The regenerative cycle of deer antlers may provide basic information on mechanisms underlying nervous system regeneration. The present contribution reviews the actual knowledge on the antler innervation and the factors responsible for its regeneration and fast growth. Growing antlers are profusely innervated by sensory fibers from the trigeminal nerve, which regenerate every year reaching elongation rates up to 2 cm a day. Antler nerves grow through the velvet in close association to blood vessels. This environment is rich in growth promoting molecules capable of inducing and guiding neurite outgrowth of rat sensory neurons in vitro. Conversely, endocrine regulation failed to show effects on neurite outgrowth in vitro, in spite of including hormones of known promoting effects on axon growth. Additional studies are needed to analyze unexplored factors promoting on growth in antlers such as electric potentials or mechanical stretch, as well as on the survival of antler innervating neurons.

Cell Specific Changes of Autophagy in a Mouse Model of Contusive Spinal Cord Injury.

Abstract: Autophagy is an essential process of cellular waist clearance that becomes altered following spinal cord injury (SCI). Details on these changes, including timing after injury, underlying mechanisms, and affected cells, remain controversial. Here we present a characterization of autophagy in the mice spinal cord before and after a contusive SCI. In the undamaged spinal cord, analysis of LC3 and Beclin 1 autophagic markers reveals important differences in basal autophagy between neurons, oligodendrocytes, and astrocytes and even within cell populations. Following moderate contusion, western blot analyses of LC3 indicates that autophagy increases to a maximum at 7 days post injury (dpi), whereas unaltered Beclin 1 expression and increase of p62 suggests a possible blockage of autophagosome clearance. Immunofluorescence analyses of LC3 and Beclin 1 provide additional details that reveal a complex, cell-specific scenario. Autophagy is first activated (1 dpi) in the severed axons, followed by a later (7 dpi) accumulation of phagophores and/or autophagosomes in the neuronal soma without signs of increased initiation. Oligodendrocytes and reactive astrocytes also accumulate phagophores and autophagosomes at 7 dpi, but whereas the accumulation in astrocytes is associated with an increased autophagy initiation, it seems to result from a blockage of the autophagic flux in oligodendrocytes. Comparison with previous studies highlights the complex and heterogeneous autophagic responses induced by the SCI, leading in many cases to contradictory results and interpretations. Future studies should consider this complexity in the design of therapeutic interventions based on the modulation of autophagy to treat SCI.

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

Abstract: In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Traumatic Spinal Cord Injury-Repair and Regeneration.

Abstract: BACKGROUND: Traumatic spinal cord injuries (SCI) have devastating consequences for the physical, financial, and psychosocial well-being of patients and their caregivers. Expediently delivering interventions during the early postinjury period can have a tremendous impact on long-term functional recovery. PATHOPHYSIOLOGY: This is largely due to the unique pathophysiology of SCI where the initial traumatic insult (primary injury) is followed by a progressive secondary injury cascade characterized by ischemia, proapoptotic signaling, and peripheral inflammatory cell infiltration. Over the subsequent hours, release of proinflammatory cytokines and cytotoxic debris (DNA, ATP, reactive oxygen species) cyclically adds to the harsh postinjury microenvironment. As the lesions mature into the chronic phase, regeneration is severely impeded by the development of an astroglial-fibrous scar surrounding coalesced cystic cavities. Addressing these challenges forms the basis of current and upcoming treatments for SCI. MANAGEMENT: This paper discusses the evidence-based management of a patient with SCI while emphasizing the importance of early definitive care. Key neuroprotective therapies are summarized including surgical decompression, methylprednisolone, and blood pressure augmentation. We then review exciting neuroprotective interventions on the cusp of translation such as Riluzole, Minocycline, magnesium, therapeutic hypothermia, and CSF drainage. We also explore the most promising neuroregenerative strategies in trial today including Cethrin™, anti-NOGO antibody, cell-based approaches, and bioengineered biomaterials. Each section provides a working knowledge of the key preclinical and patient trials relevant to clinicians while highlighting the pathophysiologic rationale for the therapies. CONCLUSION: We conclude with our perspectives on the future of treatment and research in this rapidly evolving field.

Spinal Cord Injury: Pathophysiology, Multimolecular Interactions, and Underlying Recovery Mechanisms.

Abstract: Spinal cord injury (SCI) is a destructive neurological and pathological state that causes major motor, sensory and autonomic dysfunctions. Its pathophysiology comprises acute and chronic phases and incorporates a cascade of destructive events such as ischemia, oxidative stress, inflammatory events, apoptotic pathways and locomotor dysfunctions. Many therapeutic strategies have been proposed to overcome neurodegenerative events and reduce secondary neuronal damage. Efforts have also been devoted in developing neuroprotective and neuro-regenerative therapies that promote neuronal recovery and outcome. Although varying degrees of success have been achieved, curative accomplishment is still elusive probably due to the complex healing and protective mechanisms involved. Thus, current understanding in this area must be assessed to formulate appropriate treatment modalities to improve SCI recovery. This review aims to promote the understanding of SCI pathophysiology, interrelated or interlinked multimolecular interactions and various methods of neuronal recovery i.e., neuroprotective, immunomodulatory and neuro-regenerative pathways and relevant approaches.

Purinergic Signalling: Therapeutic Developments.

Abstract: Purinergic signalling, i.e. the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes 4 subtypes of the P1 (adenosine) receptor, 7 subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventicular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y¬12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y¬12 receptor-mediated platelet aggregation. Diquafasol, a long acting P2Y¬2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes and cancer.

The emerging roles of microRNAs in CNS injuries.

Abstract: The consequences of injuries to the CNS are profound and persistent, resulting in substantial burden to both the individual patient and society. Existing treatments for CNS injuries such as stroke, traumatic brain injury and spinal cord injury have proved inadequate, partly owing to an incomplete understanding of post-injury cellular and molecular changes. MicroRNAs (miRNAs) are RNA molecules composed of 20-24 nucleotides that function to inhibit mRNA translation and have key roles in normal CNS development and function, as well as in disease. However, a role for miRNAs as effectors of CNS injury has recently emerged. Use of bioinformatics to assess the mRNA targets of miRNAs enables high-order analysis of interconnected networks, and can reveal affected pathways that may not be identifiable with the use of traditional techniques such as gene knock-in or knockout approaches, or mRNA microarrays. In this Review, we discuss the findings of miRNA microarray studies of spinal cord injury, traumatic brain injury and stroke, as well as the use of gene ontological algorithms to discern global patterns of molecular and cellular changes following such injuries. Furthermore, we examine the current state of miRNA-based therapies and their potential to improve functional outcomes in patients with CNS injuries.