scholarly journals Genetic Renal Diseases: The Emerging Role of Zebrafish Models

Cells ◽  
2018 ◽  
Vol 7 (9) ◽  
pp. 130 ◽  
Author(s):  
Mohamed Elmonem ◽  
Sante Berlingerio ◽  
Lambertus van den Heuvel ◽  
Peter de Witte ◽  
Martin Lowe ◽  
...  
Keyword(s):  
Genetic Diseases ◽  
Cost Effective ◽  
Therapeutic Interventions ◽  
Renal Diseases ◽  
Larval Zebrafish ◽  
Zebrafish Pronephros ◽  
Evaluation Techniques ◽  
Renal Phenotype

The structural and functional similarity of the larval zebrafish pronephros to the human nephron, together with the recent development of easier and more precise techniques to manipulate the zebrafish genome have motivated many researchers to model human renal diseases in the zebrafish. Over the last few years, great advances have been made, not only in the modeling techniques of genetic diseases in the zebrafish, but also in how to validate and exploit these models, crossing the bridge towards more informative explanations of disease pathophysiology and better designed therapeutic interventions in a cost-effective in vivo system. Here, we review the significant progress in these areas giving special attention to the renal phenotype evaluation techniques. We further discuss the future applications of such models, particularly their role in revealing new genetic diseases of the kidney and their potential use in personalized medicine.

scholarly journals Spinal V2b neurons reveal a role for ipsilateral inhibition in speed control

2019 ◽  
Author(s):  
Rebecca A. Callahan ◽  
Richard Roberts ◽  
Mohini Sengupta ◽  
Yukiko Kimura ◽  
Shin-ichi Higashijima ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Speed Control ◽  
Morphological Properties ◽  
Larval Zebrafish ◽  
Motor Circuits ◽  
Transgenic Lines ◽  
Left And Right ◽  
Specific Influence

AbstractThe spinal cord contains a diverse array of interneurons that govern motor output. Traditionally, models of spinal circuits have emphasized the role of inhibition in enforcing reciprocal alternation between left and right sides or flexors and extensors. However, recent work has shown that inhibition also increases coincident with excitation during contraction. Here, using larval zebrafish, we investigate the V2b (Gata3+) class of neurons, which contribute to flexor-extensor alternation but are otherwise poorly understood. Using newly generated transgenic lines we define two stable subclasses with distinct neurotransmitter and morphological properties. These two V2b subclasses make direct synapses onto motor neurons with differential targeting to slower and faster circuits. In vivo, optogenetic suppression of V2b activity leads to increases in locomotor speed. We conclude that V2b neurons exert speed-specific influence over axial motor circuits throughout the rostrocaudal axis. Together, these results indicate a new role for ipsilateral inhibition in speed control.

scholarly journals Bioluminescent Ross River Virus Allows Live Monitoring of Acute and Long-Term Alphaviral Infection by In Vivo Imaging

Viruses ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 584 ◽  
Author(s):  
Essia Belarbi ◽  
Vincent Legros ◽  
Justine Basset ◽  
Philippe Desprès ◽  
Pierre Roques ◽  
...  
Keyword(s):  
Immunosuppressive Treatment ◽  
Treatment Strategies ◽  
Chronic Phase ◽  
Therapeutic Interventions ◽  
In Vivo Evaluation ◽  
Viral Spread ◽  
Bioluminescent Signal

Arboviruses like chikungunya and Ross River (RRV) are responsible for massive outbreaks of viral polyarthritis. There is no effective treatment or vaccine available against these viruses that induce prolonged and disabling arthritis. To explore the physiopathological mechanisms of alphaviral arthritis, we engineered a recombinant RRV expressing a NanoLuc reporter (RRV-NLuc), which exhibited high stability, near native replication kinetics and allowed real time monitoring of viral spread in an albino mouse strain. During the acute phase of the disease, we observed a high bioluminescent signal reflecting viral replication and dissemination in the infected mice. Using Bindarit, an anti-inflammatory drug that inhibits monocyte recruitment, we observed a reduction in viral dissemination demonstrating the important role of monocytes in the propagation of the virus and the adaptation of this model to the in vivo evaluation of treatment strategies. After resolution of the acute symptoms, we observed an increase in the bioluminescent signal in mice subjected to an immunosuppressive treatment 30 days post infection, thus showing active in vivo replication of remnant virus. We show here that this novel reporter virus is suitable to study the alphaviral disease up to the chronic phase, opening new perspectives for the evaluation of therapeutic interventions.

scholarly journals Histone Deacetylase Inhibitors as Therapeutic Interventions on Cervical Cancer Induced by Human Papillomavirus

2021 ◽  
Vol 8 ◽  
Author(s):  
Natália Lourenço de Freitas ◽  
Maria Gabriela Deberaldini ◽  
Diana Gomes ◽  
Aline Renata Pavan ◽  
Ângela Sousa ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Human Papillomaviruses ◽  
Therapeutic Interventions ◽  
Cellular Targets

The role of epigenetic modifications on the carcinogenesis process has received a lot of attention in the last years. Among those, histone acetylation is a process regulated by histone deacetylases (HDAC) and histone acetyltransferases (HAT), and it plays an important role in epigenetic regulation, allowing the control of the gene expression. HDAC inhibitors (HDACi) induce cancer cell cycle arrest, differentiation, and cell death and reduce angiogenesis and other cellular events. Human papillomaviruses (HPVs) are small, non-enveloped double-stranded DNA viruses. They are major human carcinogens, being intricately linked to the development of cancer in 4.5% of the patients diagnosed with cancer worldwide. Long-term infection of high-risk (HR) HPV types, mainly HPV16 and HPV18, is one of the major risk factors responsible for promoting cervical cancer development. In vitro and in vivo assays have demonstrated that HDACi could be a promising therapy to HPV-related cervical cancer. Regardless of some controversial studies, the therapy with HDACi could target several cellular targets which HR-HPV oncoproteins could be able to deregulate. This review article describes the role of HDACi as a possible intervention in cervical cancer treatment induced by HPV, highlighting the main advances reached in the last years and providing insights for further investigations regarding those agents against cervical cancer.

scholarly journals Spinal V2b neurons reveal a role for ipsilateral inhibition in speed control

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Rebecca A Callahan ◽  
Richard Roberts ◽  
Mohini Sengupta ◽  
Yukiko Kimura ◽  
Shin-ichi Higashijima ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Speed Control ◽  
Morphological Properties ◽  
Larval Zebrafish ◽  
Motor Circuits ◽  
Transgenic Lines ◽  
Left And Right

The spinal cord contains a diverse array of interneurons that govern motor output. Traditionally, models of spinal circuits have emphasized the role of inhibition in enforcing reciprocal alternation between left and right sides or flexors and extensors. However, recent work has shown that inhibition also increases coincident with excitation during contraction. Here, using larval zebrafish, we investigate the V2b (Gata3+) class of neurons, which contribute to flexor-extensor alternation but are otherwise poorly understood. Using newly generated transgenic lines we define two stable subclasses with distinct neurotransmitter and morphological properties. These V2b subclasses synapse directly onto motor neurons with differential targeting to speed-specific circuits. In vivo, optogenetic manipulation of V2b activity modulates locomotor frequency: suppressing V2b neurons elicits faster locomotion, whereas activating V2b neurons slows locomotion. We conclude that V2b neurons serve as a brake on axial motor circuits. Together, these results indicate a role for ipsilateral inhibition in speed control.

Baboon Models of Acute Arterial Thrombosis

1987 ◽  
Vol 58 (03) ◽  
pp. 801-805 ◽  
Author(s):  
Stephen R Hanson ◽  
Laurence A Harker
Keyword(s):  
Molecular Biology ◽  
Arterial Thrombosis ◽  
Vascular Graft ◽  
Thrombus Formation ◽  
Cost Effective ◽  
Therapeutic Agents ◽  
Model Systems ◽  
Therapeutic Interventions ◽  
Relative Efficacy

SummaryIn conclusion, we believe that the baboon offers many advantages as an experimental animal to study vascular disease, thrombus formation and dissolution, the effects of mediating variables, and the relative efficacy of therapeutic interventions. Each specific application for testing therapeutic agents may require testing in different model systems. For example, the AV vascular graft model is efficient, cost effective and well adapted to study interventions for acute arterialthrombosis. As the antithrombotic products of genetic engineering and molecular biology emerge, it will be increasingly important to have relevant, reproducible, and quantitative approaches to evaluate their effects in vivo.

scholarly journals Dysregulation of NRAP degradation by KLHL41 contributes to pathophysiology in nemaline myopathy

2019 ◽  
Vol 28 (15) ◽  
pp. 2549-2560 ◽  
Author(s):  
Caroline Jirka ◽  
Jasmine H Pak ◽  
Claire A Grosgogeat ◽  
Michael Mario Marchetii ◽  
Vandana A Gupta
Keyword(s):  
Skeletal Muscle ◽  
Thin Filament ◽  
Muscle Development ◽  
Nemaline Myopathy ◽  
Therapeutic Interventions ◽  
Transgenic Zebrafish ◽  
Anchoring Protein ◽  
And Function

Abstract Nemaline myopathy (NM) is the most common form of congenital myopathy that results in hypotonia and muscle weakness. This disease is clinically and genetically heterogeneous, but three recently discovered genes in NM encode for members of the Kelch family of proteins. Kelch proteins act as substrate-specific adaptors for Cullin 3 (CUL3) E3 ubiquitin ligase to regulate protein turnover through the ubiquitin-proteasome machinery. Defects in thin filament formation and/or stability are key molecular processes that underlie the disease pathology in NM; however, the role of Kelch proteins in these processes in normal and diseases conditions remains elusive. Here, we describe a role of NM causing Kelch protein, KLHL41, in premyofibil-myofibil transition during skeletal muscle development through a regulation of the thin filament chaperone, nebulin-related anchoring protein (NRAP). KLHL41 binds to the thin filament chaperone NRAP and promotes ubiquitination and subsequent degradation of NRAP, a process that is critical for the formation of mature myofibrils. KLHL41 deficiency results in abnormal accumulation of NRAP in muscle cells. NRAP overexpression in transgenic zebrafish resulted in a severe myopathic phenotype and absence of mature myofibrils demonstrating a role in disease pathology. Reducing Nrap levels in KLHL41 deficient zebrafish rescues the structural and function defects associated with disease pathology. We conclude that defects in KLHL41-mediated ubiquitination of sarcomeric proteins contribute to structural and functional deficits in skeletal muscle. These findings further our understanding of how the sarcomere assembly is regulated by disease-causing factors in vivo, which will be imperative for developing mechanism-based specific therapeutic interventions.

Transgenic animal models of renal development and pathogenesis

1995 ◽  
Vol 269 (5) ◽  
pp. F601-F620 ◽  
Author(s):  
J. B. Kopp ◽  
P. E. Klotman
Keyword(s):  
Growth Factors ◽  
Renin Angiotensin System ◽  
Transgenic Animals ◽  
Cell Types ◽  
Pressure Control ◽  
Transgenic Animal ◽  
Renal Diseases ◽  
Renal Development

The use of transgenic animals represents a powerful tool with which to address the role of particular gene products in vivo. Recent technical and biological advances have simplified the process of creating both transgenic mice and null-mutation mice. Increasing numbers of genetic control elements are available to direct transgene expression to particular renal cell types and to enhance the consistency of expression. These approaches have contributed significantly to our understanding of renal development and pathogenesis, in particular in the following areas: the roles of various oncogenes, homeobox genes, and growth factors in renal development and the pathogenesis of cystic renal diseases; the contribution of systemic and local expression of the renin-angiotensin system to blood pressure control; the role of growth factors and cytokines in progressive glomerular disease; the role of viral proteins in the pathogenesis of glomerular and tubular disease; and mechanisms of immune-mediated renal disease.

scholarly journals The H3K36me2 writer-reader dependency in H3K27M-DIPG

2021 ◽  
Author(s):  
Jia-Ray Yu ◽  
Gary LeRoy ◽  
Devin Bready ◽  
Joshua D. Frenster ◽  
Ricardo Saldaña-Meyer ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Histone H3 ◽  
Pediatric Brain Tumor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Therapeutic Interventions ◽  
Functional Pathway ◽  
Proliferation In Vitro

AbstractThe lysine-to-methionine mutation at residue 27 of histone H3 (H3K27M) is a driving mutation in Diffuse Intrinsic Pontine Glioma (DIPG), a highly aggressive form of pediatric brain tumor with no effective treatment and little chance of survival. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity, the placement of methylation at lysine 27 of histone H3 (H3K27me2/3), promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation in vitro and tumorigenesis in vivo, and disrupts tumor-promoting gene expression programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers that mediate the pro-tumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Together, our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG and suggest a possibility to target this pathway for therapeutic interventions.

High Resolution Optical Microscopy Will Play a Major Role in Functional Assessments and the Prevention of Disease

2000 ◽  
Vol 6 (S2) ◽  
pp. 834-835
Author(s):  
Robert W. Bradford, Chairman ◽  
Curriculum Oversight
Keyword(s):  
Disease Onset ◽  
Accelerated Aging ◽  
Oxidative Injury ◽  
Cost Effective ◽  
Low Complexity ◽  
The Body ◽  
Functional Assessments ◽  
Complexity Cost

The typical aging processes can be characterized by a gradual alteration and essential breakdown of the functional systems of the body. Numerous factors play important roles in the alterations of these pathways from biochemical individuality and genetic predisposition to environmental insults and deficiency states.1 Clinical research, as but one example, has clearly documented the role of free radicals (ROS) or oxidative injury in disease and aging affecting the body's basic cellular structures.The objective of functional or health assessments is to be able to detect in vivo stresses and imbalances in the biological systems, while the patient is asymptomatic, so that early therapeutic intervention can resolve the problems prior to disease onset or accelerated aging. The ability to assess risk factors and treat the sub-clinical metabolic toxicities, deficiency states, hormonal imbalances, oxidative injury (ROS), immunodeficiencies, enzyme down regulations, antioxidant status, metal toxicities, cardiovascular stresses, organ reserves/stresses and detox systems in a low-complexity, cost-effective office procedure is true preventive medicine.

scholarly journals Advancements in mRNA Encoded Antibodies for Passive Immunotherapy

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 108
Author(s):  
Cailin E. Deal ◽  
Andrea Carfi ◽  
Obadiah J. Plante
Keyword(s):  
Cost Effective ◽  
Great Promise ◽  
Lead Times ◽  
Significant Progress ◽  
Passive Immunotherapy ◽  
Therapeutic Class ◽  
Medicine Today ◽  
Preclinical And Clinical Studies

Monoclonal antibodies are the fastest growing therapeutic class in medicine today. They hold great promise for a myriad of indications, including cancer, allergy, autoimmune and infectious diseases. However, the wide accessibility of these therapeutics is hindered by manufacturing and purification challenges that result in high costs and long lead times. Efforts are being made to find alternative ways to produce and deliver antibodies in more expedient and cost-effective platforms. The field of mRNA has made significant progress in the last ten years and has emerged as a highly attractive means of encoding and producing any protein of interest in vivo. Through the natural role of mRNA as a transient carrier of genetic information for translation into proteins, in vivo expression of mRNA-encoded antibodies offer many advantages over recombinantly produced antibodies. In this review, we examine both preclinical and clinical studies that demonstrate the feasibility of mRNA-encoded antibodies and discuss the remaining challenges ahead.

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