A5018076822- Muscle Physiology and Disorders
- Adipose Tissue and Metabolism
- Exercise and Physiological Responses
- Ophthalmology and Eye Disorders
- Corneal Surgery and Treatments
- Cardiomyopathy and Myosin Studies
- Retinal Diseases and Treatments
- Ocular Diseases and Behçet’s Syndrome
- Multiple Sclerosis Research Studies
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Genetics and Physical Performance
- Monoclonal and Polyclonal Antibodies Research
- Tissue Engineering and Regenerative Medicine
- Glycosylation and Glycoproteins Research
- Glaucoma and retinal disorders
- Inflammasome and immune disorders
- High Altitude and Hypoxia
- RNA regulation and disease
- Laser Applications in Dentistry and Medicine
- Pulmonary Hypertension Research and Treatments
- Corneal surgery and disorders
- Muscle metabolism and nutrition
- Cell Adhesion Molecules Research
- Ocular Surface and Contact Lens
- Virus-based gene therapy research
Atara Biotherapeutics (United States)
2022-2023
University of Pennsylvania
2006-2020
University of Kentucky
2011-2016
University of Chicago
2014-2016
Northwestern University
2016
Visual Sciences (United States)
2014
Philadelphia University
2012
California University of Pennsylvania
2011
Children's Hospital of Philadelphia
2004
Glostrup Hospital
2004
Mutations in myostatin (GDF8) cause marked increases muscle mass, suggesting that this transforming growth factor-beta (TGF-beta) superfamily member negatively regulates growth. Myostatin blockade therefore offers a strategy for reversing wasting Duchenne's muscular dystrophy (DMD) without resorting to genetic manipulation. Here, we demonstrate pharmacological using propeptide stabilized by fusion IgG-Fc improved pathophysiology of the mdx mouse model DMD. Functional benefits evidenced...
Duchenne muscular dystrophy (DMD) is caused by mutations in dystrophin and the subsequent disruption of dystrophin-associated protein complex (DAPC). Utrophin a homolog expressed at high levels developing muscle that an attractive target for DMD therapy. Here we show extracellular matrix biglycan regulates utrophin expression immature recombinant human (rhBGN) increases cultured myotubes. Systemically delivered rhBGN up-regulates sarcolemma reduces pathology mdx mouse model DMD. RhBGN...
Deficient expression of the RNase III DICER1, which leads to accumulation cytotoxic Alu RNA, has been implicated in degeneration retinal pigmented epithelium (RPE) geographic atrophy (GA), a late stage age-related macular that causes blindness millions people worldwide. Here we show increased extracellular-signal-regulated kinase (ERK) 1/2 phosphorylation RPE human eyes with GA and mouse cell culture induced by DICER1 depletion or RNA exposure is mediated via ERK1/2 signaling. overexpression...
The discovery of sequence-specific gene silencing by endogenous double-stranded RNAs (dsRNA) has propelled synthetic short-interfering (siRNAs) to the forefront targeted pharmaceutical engineering. first clinical trials utilized 21-nucleotide (nt) siRNAs for treatment neovascular age-related macular degeneration (AMD). Surprisingly, these compounds were not formulated cell permeation, which is required bona fide RNA interference (RNAi). We showed that "naked" suppress neovascularization in...
Significance Geographic atrophy is a late stage of age-related macular degeneration (AMD) that causes blindness in millions worldwide characterized by death the retinal pigmented epithelium (RPE). We previously reported RPE due to deficiency enzyme DICER1, which leads accumulation toxic Alu RNA. also demonstrated RNA activating an immune platform called NLRP3 inflammasome. However, precise mechanisms this disease remained unresolved. The present study indicates induces Caspase-8 downstream...
IL-15 receptor α (IL-15Rα) is a component of the heterotrimeric plasma membrane for pleiotropic cytokine IL-15. However, IL-15Rα not merely an subunit, as mice lacking either or have unique phenotypes. and been implicated in muscle phenotypes, but role physiology has defined. Here, we shown that loss induces functional oxidative shift fast muscles, substantially increasing fatigue resistance exercise capacity. IL-15Rα–knockout (IL-15Rα–KO) ran greater distances had ambulatory activity than...
Duchenne's muscular dystrophy (DMD) is a fatal neuromuscular disease caused by absence of dystrophin. Utrophin chromosome 6-encoded dystrophin-related protein (DRP), sharing functional motifs with Utrophin's ability to compensate for dystrophin during development and when transgenically overexpressed has provided an important impetus identifying activators utrophin expression. The promoter A transcriptionally regulated in part heregulin-mediated, extracellular signal-related kinase-dependent...
Abstract We propose that carbonic anhydrase III (CAIII) functions as an anti‐oxidant agent in skeletal muscle. To explore this hypothesis, we analyzed the gene expression profile of muscle mice deficient CAIII utilizing murine genome U74Av2 set microarray. Pairwise comparison between knockout and their wild‐type littermates revealed more than 500 12,000 genes array showed altered level transcription. Of particular note were transcriptional alterations among associated with glutathione redox...
Abstract Myostatin is a negative regulator of skeletal muscle growth. mutations and pharmacological strategies increase mass in vivo, suggesting that myostatin blockade may prove useful diseases characterized by wasting, such as the muscular dystrophies. We subjected γ‐sarcoglycan–deficient ( Sgcg −/− ) mouse model limb‐girdle dystrophy (LGMD) 2C to antibody‐mediated vivo. inhibition led increased fiber size, mass, absolute force. However, no clear improvement histopathology was evident,...
Blocking cleavage of latent TGFβ binding protein 4, a modifier muscular dystrophy in humans and mice, inhibits release decreases pathology dystrophy.
Latent TGFβ binding proteins (LTBPs) regulate the extracellular availability of latent TGFβ. LTBP4 was identified as a genetic modifier muscular dystrophy in mice and humans. An in-frame insertion polymorphism murine Ltbp4 gene associates with partial protection against dystrophy. In humans, nonsynonymous single nucleotide polymorphisms associate prolonged ambulation Duchenne To better understand its role modifying dystrophy, we created transgenic overexpressing protective allele...
Dominant and recessive mutations in collagen VI genes, COL6A1, COL6A2, COL6A3, cause a continuous spectrum of disorders characterized by muscle weakness connective tissue abnormalities ranging from the severe Ullrich congenital muscular dystrophy to mild Bethlem myopathy. Herein, we report development mouse model for dominant deleting exon 16 Col6a3 gene. The resulting heterozygous mouse, Col6a3(+/d16), produced comparable amounts normal mRNA mutant transcript with an in-frame deletion 54 bp...
Disruption of the dystrophin complex causes muscle injury, dysfunction, cell death and fibrosis. Excess transforming growth factor (TGF) β signaling has been described in human muscular dystrophy animal models, where it is thought to relate progressive fibrosis that characterizes dystrophic muscle. We now found canonical TGFβ acutely increases when stimulated contract. Muscle lacking dystrophin-associated protein γ-sarcoglycan (Sgcg null) was subjected a lengthening protocol produce maximal...
Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world's population. The most widely used anti-angiogenic drug bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits mice. Here we show suppressed three models via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved or antibodies without (adalimumab,...
Abstract Upregulation of endogenous utrophin offers great promise for treating DMD, as it can functionally compensate the lack dystrophin caused by DMD gene mutations, without immunogenic concerns associated with delivering dystrophin. However, post-transcriptional repression mechanisms targeting 5′ and 3′ untranslated regions (UTRs) mRNA significantly limit magnitude upregulation achievable promoter activation. Using a 5′3′UTR reporter assay, we performed high-throughput screen (HTS) small...