A5040229265- Sarcoma Diagnosis and Treatment
- FOXO transcription factor regulation
- Congenital heart defects research
- Virus-based gene therapy research
- Zebrafish Biomedical Research Applications
- RNA Research and Splicing
- Molecular Biology Techniques and Applications
- Genomics and Chromatin Dynamics
- Protein Degradation and Inhibitors
- Cancer-related molecular mechanisms research
- Muscle Physiology and Disorders
- Developmental Biology and Gene Regulation
- Epigenetics and DNA Methylation
- CAR-T cell therapy research
- Renal and related cancers
- Gene Regulatory Network Analysis
- RNA modifications and cancer
- Fibroblast Growth Factor Research
- Microtubule and mitosis dynamics
- Viral Infectious Diseases and Gene Expression in Insects
- Phagocytosis and Immune Regulation
- Congenital gastrointestinal and neural anomalies
- Circular RNAs in diseases
- Fish biology, ecology, and behavior
- Signaling Pathways in Disease
Nationwide Children's Hospital
2021-2025
The Ohio State University
2021-2025
The University of Texas Southwestern Medical Center
2016-2019
Southwestern Medical Center
2016-2019
University of California, Los Angeles
2012-2018
Duchenne muscular dystrophy (DMD) causes profound and progressive muscle weakness loss, resulting in early death. DMD is usually caused by frameshifting deletions the gene DMD, which leads to absence of dystrophin protein. Dystrophin binds F-actin components dystrophin-associated glycoprotein complex protects sarcolemma from contraction-induced injury. Antisense oligonucleotide-mediated exon skipping a promising therapeutic approach aimed at restoring reading frame allowing expression an...
Alveolar rhabdomyosarcoma is a pediatric soft-tissue sarcoma caused by PAX3/7-FOXO1 fusion oncogenes and characterized impaired skeletal muscle development. We developed human PAX3-FOXO1 -driven zebrafish models of tumorigenesis found that exhibits discrete cell lineage susceptibility transformation. Tumors 1.6-19 months were primitive neuroectodermal tumors or rhabdomyosarcoma. applied this transgenic model to study how leverages early developmental pathways for oncogenesis her3 unique...
Clinical sequencing efforts are rapidly identifying sarcoma gene fusions that lack functional validation. An example is the fusion of transcriptional coactivators, VGLL2-NCOA2, found in infantile rhabdomyosarcoma. To delineate VGLL2-NCOA2 tumorigenic mechanisms and identify therapeutic vulnerabilities, we implement a cross-species comparative oncology approach with zebrafish, mouse allograft, patient samples. We find sufficient to generate mesenchymal tumors display features immature...
HES3 is a basic helix-loop-helix transcription factor that regulates neural stem cell renewal during development. overexpression predictive of reduced overall survival in patients with fusion-positive rhabdomyosarcoma, pediatric cancer resembles immature and undifferentiated skeletal muscle. However, the mechanisms cooperation rhabdomyosarcoma are unclear likely related to her3/HES3's role neurogenesis. To investigate HES3's function development, we generated zebrafish CRISPR/Cas9 null...
Abstract Clinical sequencing efforts have revolutionized our approaches to categorizing pediatric cancers in real time. This has dramatically improved ability profile tumors and some circumstances identify actionable vulnerabilities personalize clinical care. Unfortunately, many of the fusion positive sarcomas are driven by oncogenic fusions that unclear mechanisms transformation lack therapeutic targets. Many these fusion-oncogenes no cell, patient derived xenograft (PDX), or animal model...
Abstract Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma that has molecular features of immature skeletal muscle. The aggressive forms rhabdomyosarcoma are driven by two genes inappropriately juxtaposed to form a fusion-oncogene. These fusion-oncogenes consists transcription factors, various chromatin regulators, and kinases obtain gain-of-function activities. Fusion-positive rhabdomyosarcomas have no targeted therapies. Patients treated general chemotherapy, surgery,...
Abstract Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma and associated with arrested skeletal muscle differentiation. RMS poses considerable challenges in both diagnosis treatment, presence of fusion oncogenes predictive more aggressive forms disease. There a lack mechanistic understanding fusion-oncogene-driven tumorigenesis. Thus, efforts need to be directed toward defining fusion-oncogene biology identify novel therapeutic strategies improve clinical outcomes...
Abstract Rhabdomyosarcoma (RMS) is most common pediatric soft tissue sarcoma, aggressive, and has characteristics of arrested skeletal muscle differentiation. Infantile RMS, a subtype genetically driven by family fusion-oncogenes involving key proteins essential for development. One example the fusion between transcriptional coactivators, VGLL2 NCOA2. Recent VGLL2::NCOA2-driven RMS cases have shown that this fusion-oncogene can be lethal; however, there lack significant knowledge surrounding...
Abstract The chimeric transcription factor PAX3::FOXO1 is a core dependency and monogenic driver of fusion-positive rhabdomyosarcoma, an aggressive pediatric soft-tissue sarcoma. consists the PAX3 DNA binding domains (paired homeobox) FOXO1 transactivation domain. Despite identification fusion-oncogene over thirty years ago, there are no targeted therapies for children suffering from this disease. current therapeutic regimen surgery, radiation, general chemotherapy, which has been largely...
Abstract Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma and associated with impaired skeletal muscle differentiation. RMS has significant diagnostic therapeutic challenges, presence of fusion oncogenes contributes to aggressiveness disease. There exists lack mechanistic understanding fusion-oncogene driven tumorigenesis. As a result, more efforts need be directed towards defining biology identify novel strategies improve clinical outcomes in patients. A new family...
Zebrafish (Danio rerio) are often anesthetized by immersion in buffered tricaine methanesulfonate (MS-222). Although commonly utilized, anesthesia presents a shortcoming of lethal asphyxiation with increased duration exposures. A newer technique that circumvents this issue, known as flow anesthesia, has been adapted from larger aquatic species to zebrafish. Flow improves safety delivering oxygen-rich water along the anesthetic across gill epithelium and allowing fish be manipulated outside...
The
ABSTRACT Survival for children with cancer has primarily improved over the past decades due to refinements in surgery, radiation and chemotherapy. Although these general therapies are sometimes curative, often recurs, resulting poor outcomes patients. Fusion-driven pediatric soft tissue sarcomas genetically defined by chromosomal translocations that create a chimeric oncogene. This distinctive, almost ‘monogenic’, genetic feature supports generation of animal models study respective diseases...
Abstract CIC-DUX4 sarcoma is a rare subtype of characterized by devastating prognosis and resistance to conventional therapeutic strategies. So far, only few models the disease have been reported, its biological mechanisms remain be elucidated. We established mosaic transgenic zebrafish expressing human fusion under control β-actin promoter. fish rapidly developed aggressive soft tissue tumors with high penetrance. RNAseq profiling revealed that shared major common targets cell lines,...
Fibroblast growth factor receptor 4 (FGFR4) has a role in many biological processes, including lipid metabolism, tissue repair, and vertebrate development. In recent years, FGFR4 overexpression activating mutations have been associated with numerous adult pediatric cancers. As such,
Duchenne muscular dystrophy (DMD) is caused by mutations in DMD, resulting loss of dystrophin, which essential to muscle health. DMD "exon skipping" uses anti-sense oligo-nucleotides (AONs) force specific exon exclusion during mRNA processing restore reading frame and rescue partially functional dystrophin protein. Although exon-skipping drugs humans show promise, levels rescued protein remain suboptimal. We previously identified dantrolene as a skip booster when combined with AON human...
Crayfish (Decapoda: Astacoidea and Parastacoidea) are among the few animals that have stem cells in hemolymph, with capacity to continuously produce differentiated neuronal structures throughout life. As use of crayfish other invertebrates increases biomedical research, we must develop laboratory standards guidelines for performing clinical procedures. This manuscript presents introductory protocols anesthesia during diagnostic imaging. Five anesthetic were evaluated: immersion buffered...
Abstract The study of cooperating genes in cancer can lead to mechanistic understanding and identifying potential therapeutic targets. To facilitate these types studies, we developed a new dual-inducible system utilizing the tetracycline- cumate-inducible systems driving HES3 PAX3::FOXO1 fusion-oncogene, respectively, as from fusion-positive rhabdomyosarcoma. With this model, independently induce expression either or PAX3::FOXO1, well simultaneously both genes. This model will allow us...
Abstract Fusion-positive rhabdomyosarcoma is an aggressive pediatric cancer lacking curative therapies, and outcomes for children with this disease have not improved in decades. The chimeric transcription factor PAX3::FOXO1 the most common lethal driver of fusion-positive rhabdomyosarcoma, it consists DNA binding domains PAX3 fused to transactivation domain FOXO1. Despite its well-established essentiality tumorigenesis, how initially generates a tumorigenic cell state has been challenging...
Abstract Fusion-positive rhabdomyosarcoma is an aggressive pediatric cancer molecularly characterized by arrested myogenesis. The defining genetic driver, PAX3::FOXO1, functions as a chimeric gain-of-function transcription factor. An incomplete understanding of PAX3::FOXO1’s in vivo epigenetic mechanisms has hindered therapeutic development. Here, we establish PAX3::FOXO1 zebrafish injection model and semi-automated ChIP-seq normalization strategy to evaluate how initially interfaces with...
We report a universal strategy for 2D chromatin sequencing, to increase uniform data analyses and sharing across labs, facilitate highly quantitative comparisons experimental conditions. Within our system, we provide wetlab drylab tools researchers establish analyze protein-genome binding with PerCell ChIP-seq. Our methodology is virtually no cost flexible, enabling rapid, quantitative, internally normalized sequencing catalyze project development in variety of systems, including vivo...
Abstract Fusion-positive rhabdomyosarcoma is an aggressive pediatric cancer with features of arrested skeletal muscle development. PAX3::FOXO1 the most common and lethal fusion-oncogene this disease arises from a translocation between DNA binding domains PAX3 transactivation domain FOXO1. This chimeric transcription factor required for tumor initiation has pioneering activity allowing it unique potential to bind inaccessible chromatin make regions amenable transcription. Despite...