A5081097332- Muscle Physiology and Disorders
- Virus-based gene therapy research
- Nerve injury and regeneration
- Genetic and rare skin diseases.
- Cancer and Skin Lesions
- Pancreatic function and diabetes
- Hedgehog Signaling Pathway Studies
- Metabolism, Diabetes, and Cancer
- Exercise and Physiological Responses
- Cerebral Venous Sinus Thrombosis
- Diagnosis and Treatment of Venous Diseases
- Diet, Metabolism, and Disease
- Biotin and Related Studies
- Wound Healing and Treatments
- Hormonal Regulation and Hypertension
- Pituitary Gland Disorders and Treatments
- Signaling Pathways in Disease
- Neurosurgical Procedures and Complications
- Adipose Tissue and Metabolism
- Adrenal Hormones and Disorders
- Reproductive Physiology in Livestock
- Congenital heart defects research
- Reproductive System and Pregnancy
- Neurogenetic and Muscular Disorders Research
- Wnt/β-catenin signaling in development and cancer
AstraZeneca (United Kingdom)
2020-2024
University of Oxford
2003-2021
Genomics (United Kingdom)
2011-2015
KU Leuven
2005
Centre for Human Genetics
2002-2004
University of Birmingham
2000
Duchenne muscular dystrophy (DMD) is a lethal, progressive muscle wasting disease caused by loss of sarcolemmal bound dystrophin, which results in the death fibers leading to gradual depletion skeletal muscle. There significant evidence demonstrating that increasing levels dystrophin-related protein, utrophin, mouse models utrophin and prevents pathology. The aim this work was develop small molecule increases thus has therapeutic potential.We describe vivo activity SMT C1100; first orally...
Heterozygous mutations of GATA3, which encodes a dual zinc-finger transcription factor, cause hypoparathyroidism with sensorineural deafness and renal dysplasia. Here, we have investigated the role GATA3 in parathyroid function by challenging Gata3+/- mice diet low calcium vitamin D so as to expose any defects function. This led higher mortality among compared Gata3+/+ mice. Compared their wild-type littermates, had lower plasma concentrations hormone (PTH) smaller glands reduced Ki-67...
Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by dystrophin deficiency. In normal muscle, helps maintain sarcolemmal stability. Dystrophin also recruits neuronal nitric oxide synthase (nNOS) to the sarcolemma. Failure anchor nNOS membrane leads functional ischemia and aggravates in DMD. Over past two decades, great variety of therapeutic modalities have been explored treat A particularly attractive approach increase utrophin expression. Utrophin shares considerable...
Treatment options for idiopathic intracranial hypertension are limited. The enzyme 11β-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations pressure hypertension. We assessed therapeutic efficacy, safety tolerability investigated indicators of vivo efficacy the inhibitor AZD4017 compared placebo A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial 12-week...
Abstract Background The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) determines prereceptor metabolism and activation of glucocorticoids within peripheral tissues. Its dysregulation has been implicated in a wide array metabolic diseases, leading to the development selective 11β-HSD1 inhibitors. We examined impact reversible competitive inhibitor, AZD4017, on profile an overweight female cohort with idiopathic intracranial hypertension (IIH). Methods conducted UK multicenter...
ATP2C1, encoding the human secretory pathway Ca2+/Mn2+ ATPase (hSPCA1), was recently identified as defective gene in Hailey-Hailey Disease (HHD), an autosomal dominant skin disorder characterized by persistent blisters and erosions. To investigate underlying cause of HHD, we have analyzed changes expression level function hSPCA1 caused mutations found HHD patients. Mutations were introduced into hSPCA1d, a novel splice variant expressed keratinocytes, described here for first time. Encoded...
Chronic wounds (e.g. diabetic foot ulcers) reduce the quality of life, yet treatments remain limited. Glucocorticoids (activated by enzyme 11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1) impair wound healing.
The Glucokinase Regulatory Protein GKRP, encoded by GCKR, enables acute regulation of liver glucokinase to support metabolic demand. common human GCKR rs1260326:Pro446 > Leu variant within a large linkage disequilibrium region associates with pleiotropic traits including lower Type 2 diabetes risk and raised blood triglycerides cholesterol. Whether the GCKR-P446 L substitution is causal lipids unknown. We determined whether mouse GKRP phenocopies GKRP:P446 studied GKRP:P446L knockin identify...
Little is known of the transfer and maintenance machinery IncP-9 plasmids, which are found in Pseudomonas spp. include both degradative resistance plasmids. One such plasmid, pM3, confers to streptomycin tetracycline, was repeatedly species from numerous locations Belarus. pM3 has a broad host range, but unable replicate enterobacteria at 37 °C above. A mini derivative, pMT2, constructed by partial PstI digestion ligation with fragment encoding KmR. The complete sequence pMT2 determined....
Glucokinase activators (GKAs) have been developed as blood glucose lowering drugs for type 2 diabetes. Despite good short-term efficacy, several GKAs showed a decline in efficacy chronically during clinical trials. The underlying mechanisms remain incompletely understood. We tested the hypothesis that deficiency liver glucokinase regulatory protein (GKRP) occurs with common human GCKR variants affects chronic GKA efficacy. used Gckr-P446L mouse model exonic rs1260326 (P446L) variant and...
Abstract Aim To test the hypothesis that glucokinase activators (GKAs) induce hepatic adaptations alter intra‐hepatocyte metabolite homeostasis. Methods C57BL/6 mice on a standard rodent diet were treated with GKA (AZD1656) acutely or chronically. Hepatocytes isolated from after 4 8 weeks of treatment for analysis cellular metabolites and gene expression in response to substrate challenge. Results Acute exposure AZD1656 liver‐selective (PF‐04991532), before glucose tolerance test, challenge...
Abstract Context The causative link between circulating glucocorticoid excess and osteoporosis is well-established. enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which increases local cortisol production, expressed in human osteoblasts its activity with age. Objective We hypothesized that 11β-HSD1 might mediate an age-related decrease bone formation selective inhibition may enhance formation. Methods A dual-center, phase II, randomized, double-blind, placebo-controlled trial of...
The increase in uterine oxytocin receptor concentrations over the late luteal phase of oestrous cycle sheep is thought to play an important role regulation duration by facilitating effect on prostaglandin release. Experiments indicated that mRNA expression endometrium was high at oestrus compared with days 2, 7 and 12 cycle. amount pituitary gland did not show any significant differences during Oxytocin cDNA obtained characterized from ovine day 15 cycle, using RT-PCR techniques, study...