A5050037930- Pancreatic function and diabetes
- Adipose Tissue and Metabolism
- Metabolism, Diabetes, and Cancer
- Regulation of Appetite and Obesity
- Bone Metabolism and Diseases
- RNA modifications and cancer
- Parathyroid Disorders and Treatments
- Genetic Syndromes and Imprinting
- Bone health and osteoporosis research
- Aldose Reductase and Taurine
- RNA Research and Splicing
- Genetic and Kidney Cyst Diseases
- Biomedical Research and Pathophysiology
- Amyotrophic Lateral Sclerosis Research
- Pituitary Gland Disorders and Treatments
- Dermatological and Skeletal Disorders
- Kidney Stones and Urolithiasis Treatments
- Diabetes and associated disorders
- Growth Hormone and Insulin-like Growth Factors
- Bone and Dental Protein Studies
- Nuclear Receptors and Signaling
- Olfactory and Sensory Function Studies
- Neurogenetic and Muscular Disorders Research
- Diet, Metabolism, and Disease
- Vitamin D Research Studies
Mary Lyon Centre at MRC Harwell
2015-2024
Universidad Complutense de Madrid
2023
Medical Research Council
2008-2022
University College London
2010
Drexel University
2009
Graduate Theological Union
2005
Recent evidence suggests that the surface fluid secreted by human airway epithelial cells contains antimicrobial activity. The identification of factor(s) responsible for antibacterial activity in may bring new insights into lung defense mechanisms and pathogenesis disease. Defensins are small cationic peptides with broad-spectrum activity, therefore candidates bacterial killing factor fluid. They produced mucosal epithelia neutrophils several species. To date no defensins have been isolated...
Neonatal diabetes is a rare monogenic form of that usually presents within the first six months life. It commonly caused by gain-of-function mutations in genes encoding Kir6.2 and SUR1 subunits plasmalemmal ATP-sensitive K+ (KATP) channel. To better understand this disease, we generated mouse expressing mutation (V59M) causes neonatal humans used Cre-lox technology to express specifically pancreatic beta cells. These beta-V59M mice developed severe soon after birth, 5 weeks age, blood...
Craniofacial defects involving the lip and/or palate are among most common human birth defects. X-linked cleft and ankyloglossia results from loss-of-function mutations in gene encoding T-box transcription factor TBX22. Further studies show that TBX22 also found around 5% of non-syndromic patients. Although obvious at birth, underlying developmental pathogenesis remains unclear. Here, we report a Tbx22(null) mouse, which has submucous (SMCP) ankyloglossia, similar to phenotype, with small...
Physiological studies of mice are facilitated by normal plasma and 24-hour urinary reference ranges, but variability these parameters may increase due to stress that is induced housing in metabolic cages. We assessed daily weight, food water intake, urine volume final day measurements the following: sodium, potassium, chloride, urea, creatinine, calcium, phosphate, alkaline phosphatase, albumin, cholesterol glucose; glucose protein 24- 30-week-old C3H/HeH, BALB/cAnNCrl C57BL/6J mice. Between...
Mutations in genes essential for mitochondrial function have pleiotropic effects. The mechanisms underlying these traits yield insights into metabolic homeostasis and potential therapies. Here we report the characterization of a mouse model harboring mutation tryptophanyl-tRNA synthetase 2 (Wars2) gene, encoding mitochondrial-localized WARS2 protein. This hypomorphic allele causes progressive tissue-specific pathologies, including hearing loss, reduced adiposity, adipose tissue dysfunction,...
A serious adverse clinical effect of glucocorticoid steroid treatment is secondary osteoporosis, enhancing fracture risk in bone. This rapid increase bone largely independent loss (quantity), and must therefore arise from degradation the quality matrix at micro- nanoscale. However, we lack an understanding both specific alterations n steroid-induced osteoporosis as well mechanistic effects these changes. Here demonstrate nanostructural parameters mineralized fibrillar collagen matrix, which...
Renal fibrosis is a common feature of renal failure resulting from multiple aetiologies, including diabetic nephropathy, hypertension and inherited disorders. However, the mechanisms are incompletely understood we therefore explored these by establishing mouse model for tubular disorder, referred to as autosomal dominant tubulointerstitial kidney disease (ADTKD) due missense uromodulin (UMOD) mutations (ADTKD-UMOD). ADTKD-UMOD, which associated with retention mutant in endoplasmic reticulum...
The obesity-linked FTO regulatory circuitry shows cross-species molecular, cellular, metabolic, and organismal conservation.
Hypercalciuria is a major cause of nephrolithiasis, and common complex disorder involving genetic environmental factors. Identification factors for monogenic forms hypercalciuria hampered by the limited availability large families, to facilitate such studies, we screened in mice from an N-ethyl-N-nitrosourea mutagenesis programme. We identified mouse with autosomal dominant (HCALC1). Linkage studies mapped Hcalc1 locus 11.94 Mb region on chromosome 6 containing transient receptor potential...
The calcium-sensing receptor (CaSR) is a family C G-protein–coupled that plays pivotal role in extracellular calcium homeostasis. CaSR also highly expressed pancreatic islet α- and β-cells secrete glucagon insulin, respectively. To determine whether the may influence systemic glucose homeostasis, we characterized mouse model with germline gain-of-function mutation, Leu723Gln, referred to as Nuclear flecks (Nuf). Heterozygous- (CasrNuf/+) homozygous-affected (CasrNuf/Nuf) mice were shown have...
A protein altering variant in the gene encoding zinc finger homeobox-3 (ZFHX3) has recently been associated with lower BMI a human genome-wide association study. We investigated metabolic parameters mice harboring missense mutation Zfhx3 (Zfhx3
Here we report the first cloned N-ethyl-nitrosourea (ENU)-derived mouse model of diabetes. GENA348 was identified through free-fed plasma glucose measurement, being more than 2 SDs above population mean a cohort >1,201 male ENU mutant mice. The underlying gene mapped to maturity-onset diabetes young (MODY2) homology region chromosome 11 (logarithm odds 6.0). Positional candidate analyses revealed an A T transversion mutation in exon 9 glucokinase gene, resulting isoleucine...
Cushing's syndrome, which is characterized by excessive circulating glucocorticoid concentrations, may be due to ACTH-dependent or -independent causes that include anterior pituitary and adrenal cortical tumors, respectively. ACTH secretion stimulated CRH, we report a mouse model for syndrome an N-ethyl-N-nitrosourea (ENU) induced Crh mutation at -120 bp of the promoter region, significantly increased luciferase reporter activity was thus gain-of-function mutation. Crh(-120/+) mice, when...
Mutations in the skeletal muscle channel (SCN4A), encoding Nav1.4 voltage-gated sodium channel, are causative of a variety channelopathies, including non-dystrophic myotonias and periodic paralysis. The effects many these mutations on function have been characterized both vitro vivo. However, little is known about consequences SCN4A downstream from their impact electrophysiology channel. Here we report discovery novel mutation (c.1762A>G; p.I588V) patient with myotonia paralysis, located...
Glucocorticoid-induced osteoporosis (GIOP) is a major secondary form of osteoporosis, with the fracture risk significantly elevated - at similar levels bone mineral density in patients taking glucocorticoids compared non-users. The adverse structural changes multiple hierarchical GIOP, and their mechanistic consequences leading to reduced load-bearing capacity, are not clearly understood. Here we combine experimental X-ray nanoscale mechanical imaging analytical modelling matrix mechanics...
Abstract The proprotein convertase subtilisin/Kexin type 1 (PCSK1/PC1) protein processes inactive pro-hormone precursors into biologically active hormones in a number of neuroendocrine and endocrine cell types. Patients with recessive mutations PCSK1 exhibit complex spectrum traits including obesity, diarrhoea disorders. We describe here new mouse model point mutation the Pcsk1 gene that exhibits hyperphagia, transient hyperproinsulinaemia, phenotypes consistent human patient traits. results...
Steroid 5β-reductase (AKR1D1) plays important role in hepatic bile acid synthesis and glucocorticoid clearance. Bile acids glucocorticoids are potent metabolic regulators, but whether AKR1D1 controls phenotype vivo is unknown. Akr1d1 –/– mice were generated on a C57BL/6 background. Liquid chromatography/mass spectrometry, metabolomic transcriptomic approaches used to determine effects homeostasis. Metabolic phenotypes including body weight composition, lipid homeostasis, glucose tolerance...
Bardet-Biedl syndrome (BBS), a ciliopathy, is rare genetic condition characterised by retinal degeneration, obesity, kidney failure, and cognitive impairment. In spite of progress made in our general understanding BBS aetiology, the molecular cellular mechanisms underlying impairment remain elusive. Here, we report that loss proteins causes synaptic dysfunction principal neurons, providing possible explanation for phenotype observed patients. Using synaptosomal proteomics...
Abstract The analysis of volatile organic compounds (VOCs) as a non-invasive method for disease monitoring, such type 2 diabetes (T2D) has shown potential over the years although not yet set in clinical practice. Longitudinal studies to date are limited and understanding underlying VOC emission age is poorly understood. This study investigated longitudinal changes VOCs present faecal headspace two mouse models T2D – Cushing’s syndrome single Afmid knockout mice. bodyweight, blood glucose...
ABSTRACT The small GTPase ARF family member ARL15 gene locus is associated in population studies with increased risk of type 2 diabetes, lower adiponectin and higher fasting insulin levels. Previously, loss was shown to reduce secretion a human β-cell line loss-of-function mutations are found some lipodystrophy patients. We set out understand the role adipogenesis showed that endogenous palmitoylated localised Golgi mouse liver. Adipocyte overexpression palmitoylation-deficient resulted...
Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by significant metabolic disruptions, including weight loss and hypermetabolism in both patients animal models. Leptin, an adipose-derived hormone, displays altered levels ALS. Genetically reducing leptin (Lepob/+) to maintain body improved motor performance extended survival female SOD1G93A mice, although the exact molecular mechanisms behind these effects remain elusive. Here, we corroborated...
Abstract Adipose models have been applied to mechanistic studies of metabolic diseases (such as diabetes) and the subsequent discovery new therapeutics. However, typical are either insufficiently complex (2D cell cultures) or expensive labor intensive (mice/ in vivo ). To bridge gap between these order better inform pre-clinical we developed a drug-responsive 3D model white adipose tissue (WAT). Here, spheroids (680 ± 60 μ m) comprising adipogenic 3T3-L1 cells encapsulated matrix were...