A5089607333- Heterotopic Ossification and Related Conditions
- Wnt/β-catenin signaling in development and cancer
- Parathyroid Disorders and Treatments
- Medical Imaging and Pathology Studies
- Hedgehog Signaling Pathway Studies
- Cancer-related gene regulation
- Hemoglobinopathies and Related Disorders
- Knee injuries and reconstruction techniques
- Erythropoietin and Anemia Treatment
- Osteoarthritis Treatment and Mechanisms
- Iron Metabolism and Disorders
- Skin and Cellular Biology Research
- Dermatology and Skin Diseases
- Adrenal Hormones and Disorders
- Bone Metabolism and Diseases
- Total Knee Arthroplasty Outcomes
- TGF-β signaling in diseases
- Connective tissue disorders research
- Cancer and Skin Lesions
- Genetic Syndromes and Imprinting
- Vitamin D Research Studies
- Cardiovascular Effects of Exercise
- Cancer-related Molecular Pathways
- Cancer Cells and Metastasis
- Estrogen and related hormone effects
Regeneron (United States)
2013-2024
New York University
2001-2013
Georgetown University Medical Center
2003
Georgetown University
2003
Queen Mary University of London
2000-2001
Desmosomes are major cell adhesion junctions, particularly prominent in the epidermis and cardiac tissue important for rigidity strength of cells. The desmosome consists several proteins, which desmoplakin is most abundant. Here, we describe first recessive human mutation, 7901delG, gene causes a generalized striate keratoderma affecting palmoplantar epidermis, woolly hair dilated left ventricular cardiomyopathy. A number patients with this syndromic disorder suffer heart failure their...
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodically exuberant heterotopic ossification (HO), whereby skeletal muscle abnormally converted into misplaced, but histologically normal bone. This HO leads to progressive immobility with catastrophic consequences, including death asphyxiation. FOP results from mutations in the intracellular domain of type I BMP (bone morphogenetic protein) receptor ACVR1; most common mutation alters arginine 206...
Tissue-specific manifestations of the congenital bone-forming syndrome FOP are mediated by multiple tissue-resident stem cell populations.
Sclerostin is expressed by osteocytes and has catabolic effects on bone. It been shown to antagonize bone morphogenetic protein (BMP) and/or Wnt activity, although at present the underlying mechanisms are unclear. Consistent with previous findings, opposed direct Wnt3a-induced but not BMP7-induced responses when both ligand antagonist were provided exogenously cells. However, we found that proteins in same cell, sclerostin can BMP signaling directly inhibiting BMP7 secretion. interacts...
Conditional mutagenesis is becoming a method of choice for studying gene function, but constructing conditional alleles often laborious, limited by target structure, and at times, prone to incomplete ablation. To address these issues, we developed technology termed conditionals inversion (COIN). Before activation, COINs contain an inverted module (COIN module) that lies inertly within the antisense strand resident gene. When into sense site-specific recombinase, COIN causes termination...
Type 1 diabetes mellitus (T1DM) patients have osteopenia and impaired fracture healing due to decreased osteoblast activity. Further, no adequate treatments are currently available that can restore in T1DM; hence a significant need exists investigate new therapeutics for treatment of orthopedic complications. Sclerostin (SOST), WNT antagonist, negatively regulates bone formation, SostAb is potent anabolic agent. To determine whether SOST antibody (SostAb) improves streptozotocin (STZ)...
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder that characterized by episodic yet cumulative heterotopic ossification (HO) in skeletal muscles, tendons, and ligaments over patient's lifetime. FOP caused missense mutations the type I bone morphogenetic protein (BMP) receptor ACVR1. We have determined formation of requires activation mutant ACVR1 Activin A, part showing prophylactic inhibition A blocks HO mouse model FOP. Here we piece together natural...
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder whose most debilitating pathology progressive and cumulative heterotopic ossification (HO) of skeletal muscles, ligaments, tendons, fascia. FOP caused by mutations in the type I BMP receptor gene ACVR1, which enable ACVR1 to utilize its natural antagonist, activin A, as an agonistic ligand. The physiological relevance this property underscored fact that HO exquisitely dependent on activation FOP-mutant effect countered...
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodic yet cumulative heterotopic ossification (HO) of skeletal muscles, tendons, ligaments, and fascia. FOP arises from missense mutations in Activin Receptor type I (ACVR1), bone morphogenetic protein (BMP) receptor. Although initial findings implicated constitutive activity FOP-variant ACVR1 (ACVR1FOP) and/or hyperactivation BMPs, it was later shown that HO requires activation ACVR1FOP A. Inhibition...
The Hedgehog pathway is vital for the development of many epidermal appendages, but its role in mammary has been unclear. Here, we show that although Gli2 and Gli3 are expressed during embryonic development, transcriptional reporters positive signaling absent. Nevertheless, Gli3(xt/xt) embryos aberrant early marker expression lack two pairs buds, demonstrating essential bud formation preceding patterning events. Misactivation by targeted constitutive activator Gli1, from promoter Gli3(xt/+)...
Joint injury causes post-traumatic osteoarthritis (PTOA). About ∼50% of patients rupturing their anterior cruciate ligament (ACL) will develop PTOA within 1-2 decades the injury, yet mechanisms responsible for development after joint are not well understood. In this study, we examined whole gene expression by RNA sequencing (RNAseq) at 1 day, 1-, 6-, and 12 weeks post in a non-invasive tibial compression (TC) overload mouse model that mimics ACL rupture humans. We identified 1446 genes...
Patients with anterior cruciate ligament (ACL) rupture are two times as likely to develop posttraumatic osteoarthritis (PTOA). Annually, there ∼900,000 knee injuries in the United States, which account for ∼12% of all (OA) cases. PTOA leads reduced physical activity, deconditioning musculoskeletal system, and severe cases requires joint replacement restore function. Therefore, treatments that would prevent cartilage degradation post-injury provide attractive alternatives surgery. Sclerostin...
Canonical Wnt/β-catenin signaling regulates stem/progenitor cells and, when perturbed, induces many human cancers. A significant proportion of breast cancer is associated with loss secreted Wnt antagonists and mice expressing MMTV-Wnt1 MMTV-ΔN89β-catenin develop mammary adenocarcinomas. Many studies have assumed these mouse models to be equivalent. Here we show that transgenes induce tumors different phenotypes. Using axin2/conductin reporter genes activate canonical within distinct...
Wnt3a is a major regulator of bone metabolism however, very few its target genes are known in bone. preferentially signals through transmembrane receptors Frizzled and co-receptors Lrp5/6 to activate the canonical signaling pathway. Previous studies have shown that Wnt Lrp5 Lrp6 also play an essential role normal postnatal homeostasis, yet, little about specific contributions by these Wnt3a-dependent signaling. We used high-throughput sequencing technology identify regulated osteoblasts...
Anterior cruciate ligament (ACL) injuries often result in post-traumatic osteoarthritis (PTOA). To better understand the molecular mechanisms behind PTOA development following ACL injury, we profiled injury-induced transcriptional changes knee joints of three mouse strains with varying susceptibility to OA: STR/ort (highly susceptible), C57BL/6J (moderately susceptible) and super-healer MRL/MpJ (not susceptible). Right mice were injured using a non-invasive tibial compression injury model...
Non-bone in vivo micro-CT imaging has many potential applications for preclinical evaluation. Specifically, the quantification of changes vascular network and organ morphology small animals, associated with emergence progression diseases like bone fracture, inflammation cancer, would be critical to development evaluation new therapies same. However, there are few published papers describing due technical challenges, such as low image quality vessel contrast surrounding tissues. These studies...
A considerable body of circumstantial data suggests that cyclin D1 is an attractive candidate to mediate the effects β-catenin in mammary tissue. To test functional significance these correlative findings, we investigated genetic interaction between transcriptionally active (ΔN89β-catenin) and its target gene mouse gland during pubertal development, pregnancy, tumorigenesis. Our demonstrate dispensable for ΔN89β-catenin-stimulated initiation alveologenesis virgin females, de novo induction...