A5020505790- Pulmonary Hypertension Research and Treatments
- Renal and related cancers
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- ATP Synthase and ATPases Research
- Mitochondrial Function and Pathology
- Cancer Cells and Metastasis
- Pluripotent Stem Cells Research
- Ion Transport and Channel Regulation
- Cancer Immunotherapy and Biomarkers
- Erythrocyte Function and Pathophysiology
- Pediatric Hepatobiliary Diseases and Treatments
- Atherosclerosis and Cardiovascular Diseases
- Redox biology and oxidative stress
- Connective tissue disorders research
- Organ Transplantation Techniques and Outcomes
- Selenium in Biological Systems
- Caveolin-1 and cellular processes
- Chemotherapy-induced organ toxicity mitigation
- 3D Printing in Biomedical Research
- Acute Kidney Injury Research
- NF-κB Signaling Pathways
- Renal cell carcinoma treatment
- Lipid metabolism and disorders
- Organ Donation and Transplantation
- Heat shock proteins research
National Institute for Health Research
2012-2024
University of Cambridge
2010-2024
Addenbrooke's Hospital
2004-2017
Papworth Hospital
2010-2017
Central South University
2010
Justus-Liebig-Universität Gießen
2010
Hammersmith Hospital
2009
Royal Belfast Hospital for Sick Children
2009
Yale University
2004
University of Rochester
2004
Heterozygous germ-line mutations in the bone morphogenetic protein type-II receptor (BMPR-II) gene underlie heritable pulmonary arterial hypertension (HPAH). Although inflammation promotes PAH, mechanisms by which and BMPR-II dysfunction conspire to cause disease remain unknown. Here we identify that tumour necrosis factor-α (TNFα) selectively reduces transcription mediates post-translational cleavage via sheddases, ADAM10 ADAM17 artery smooth muscle cells (PASMCs). TNFα-mediated suppression...
Apoptosis signal-regulating kinase 1 (ASK1) mediates cytokines and oxidative stress (ROS)-induced apoptosis in a mitochondria-dependent pathway. However, the underlying mechanism has not been defined. In this study, we show that ASK1 is localized both cytoplasm mitochondria of endothelial cells (ECs) where it binds to cytosolic (Trx1) mitochondrial thioredoxin (Trx2), respectively. Cys-250 Cys-30 N-terminal domain are critical for binding Trx1 Trx2, Mutation at C250 enhanced ASK1-induced JNK...
Severe pulmonary arterial hypertension (PAH) is characterized by the formation of plexiform lesions and concentric intimal fibrosis in small arteries. The origin cells contributing to these vascular uncertain. Endogenous endothelial progenitor are potential contributors this process.
Exosomes are small extracellular vesicles, approximately 50 nm in diameter, derived from the endocytic pathway and released by a variety of cell types. Recent data indicate spectrum exosomal functions, including RNA transfer, antigen presentation, modulation apoptosis, shedding obsolete protein. all nephron segments also present human urine, where their function is unknown. Although one report suggested vitro uptake exosomes renal cortical collecting duct cells, most studies urinary have...
Rationale : Mutations in the bone morphogenetic protein type II receptor (BMPR-II) are responsible for majority of cases heritable pulmonary arterial hypertension (PAH). lead to reduced Smad1/5-driven expression inhibitor DNA binding 1 (Id1) and loss growth suppressive effects BMPs. The impact existing PAH therapies on BMP signaling is lacking. Objective Because prostacyclin analogues effective treatments clinical PAH, we hypothesized that these agents enhance Smad1/Id1 signaling. Methods...
Bone morphogenetic protein type II receptor (BMPR-II) mutations are responsible for over 70% of cases heritable pulmonary arterial hypertension (PAH). Loss BMP signaling promotes vascular remodeling via modulation artery smooth muscle cell (PASMC) proliferation. Id proteins (Id1-4) major downstream transcriptional targets signaling. However, the impact BMPR-II mutation on expression range and contribution individual to abnormal PASMC function remain unclear. Human PASMCs were used determine...
V-type or H+-ATPases are a family of ATP-dependent proton pumps that move protons across the plasma membrane at specialized sites such as kidney epithelial cells and osteoclasts well acidifying intracellular compartments. The 100-kDa polytopic a-subunit this group ATPases is suggested to play an important role in coupling two functions pump, ATP hydrolysis transport. In man, different isoforms encoded by four genes. ATP6V0A4 encodes a4, which expressed apically α-intercalated both human...
Human T regulatory cells (T regs) express high levels of TNF receptor 2 (TNFR2). Ligation TNFR2 with TNF, which can recognise both TNFR1 and TNFR2, or a TNFR2-selective binding molecule, DARPin 18 (D18) activates canonical NF-κB signalling, assessed by IκBα degradation, the magnitude response correlates level expression. RNA-seq analysis TNF- D18-treated human regs revealed that ligation induces transcription NFKB2 RELB, encoding proteins form non-canonical factor. In combination IL2, D18...
The ubiquitous multisubunit vacuolar-type proton pump (H<sup>+</sup>- or V-ATPase) is essential for acidification of diverse intracellular compartments. It also present in specialized forms at the plasma membrane intercalated cells distal nephron, where it required urine acidification, and osteoclasts, playing an important role bone resorption by acid secretion across ruffled border membrane. was reported previously that, human, several renal pump's constituent subunits are encoded genes...
The specialized H(+)-ATPases found in the inner ear and acid-handling cells renal collecting duct differ from those at other sites, as they contain tissue-specific subunits, such a4 B1, kidney, C2, d2, G3 well. These subunits replace ubiquitously expressed forms. Previously, we have shown that, major organs of both mouse man, subunit expression is limited to kidney. Here wide-spread transcription murine specific segments microdissected nephron, demonstrated additional epithelial fragments...
// Rafia S Al-Lamki 1 , Jun Wang Yang Natalie Burrows 2 Patrick H Maxwell Timothy Eisen 3 Anne Y Warren 4 Sakari Vanharanta 5 Simon Pacey Peter Vandenabeele 6 Jordan Pober 7 John R Bradley Department of Medicine, NIHR Cambridge Biomedical Research Centre, University Cambridge, CB2 0QQ, UK School Clinical Institute Medical Research, Campus, 0XY, Oncology, Pathology, Addenbrooke's Hospital, MRC Cancer Unit, Hutchison/MRC 0XZ, VIB Inflammation Center, Ghent University, UGhent-VIB Building FSVM,...
Abstract Inhibition of DNA binding proteins 1 and 3 (ID1 ID3) are important downstream targets BMP signalling that necessary for embryonic development. However, their specific roles in regulating the pluripotency human stem cells (hESCs) remain unclear. Here, we examined ID1 ID3 primed naive-like hESCs showed knockout lines (IDs KO) exhibited decreased survival both state. IDs KO state also tended to undergo pluripotent dissolution ectodermal differentiation. impeded primed-to-naive...
Anion exchanger-1 (AE1) mediates chloride-bicarbonate exchange across the plasma membranes of erythrocytes and, via a slightly shorter transcript, kidney epithelial cells. On an omnivorous human diet, AE1 is mainly active basolaterally in α-intercalated cells collecting duct, where it functionally coupled with apical proton pumps to maintain normal acid-base homeostasis. The C-terminal tail has important role its polarized membrane residency. We have identified β1 subunit Na(+),K(+)-ATPase...
Clear cell renal carcinoma (ccRCC) contains cancer stem-like cells (CSCs) that express CD133 (ccRCC-CD133+). CSCs are rarely in cycle and, as nonproliferating cells, resist most chemotherapeutic agents. Previously, we reported tumor necrosis factor receptor-2 (TNFR2) signaling promotes the entry of ccRCC-CD133+CSCs, rendering them susceptible to cell-cycle-dependent chemotherapeutics. Here, describe a TNFR2-activated pathway ccRCC-CD133+CSCs is required for survival. Wild-type (wt)TNF or...
Clear-cell renal cell carcinoma (ccRCC), a tubular epithelial malignancy, secretes tumor necrosis factor (TNF), which signals ccRCC cells in an autocrine manner via two surface receptors, TNFR1 and TNFR2, to activate shared distinct signaling pathways. Selective ligation of TNFR2 drives cycle entry malignant pathway involving tyrosine kinase, vascular endothelial growth receptor type 2, phosphatidylinositol-3-kinase, Akt,
Tumor necrosis factor receptor 2 (TNFR2) is strongly upregulated on renal tubular epithelial cells by acute cell-mediated rejection (ACR. In human kidney organ culture, TNFR2 signaling both upregulates expression and promotes cell cycle entry of cells. We find significantly more express CD133 mRNA protein, a putative stem marker, in allograft biopsy samples with ACR compared to injury without or pretransplant "normal kidney" samples. Of CD133+ cells, ~85% are within injured tubules ~15%...
Introduction and Objectives There is no effective pharmacological treatment for acute lung injury (ALI).Statins are a potential new therapy as they modify many of the underlying processes important in ALI.The aim this study was to test whether statins reduce inflammation improve clinical outcomes ALI.Methods We conducted randomised double-blind placebo-controlled trial patients with ALI.Patients received 80 mg simvastatin or placebo up 14 days.Measures pulmonary non-pulmonary organ function...
Deficiency of bone morphogenetic protein type II receptor (BMPRII) signaling has been implicated in the pathology pulmonary arterial hypertension (PAH). BMP ligands activate and also enhance <i>BMPR2</i> transcription. A small molecule upregulator with low toxicity may be a tractable approach to treat PAH. We used dual reporter driven specifically human embryonic stem cell (hESC)-derived endothelial cells (ECs) identify novel piperidine, BUR1 that increase Id1 expression. The sequential drug...
<h3>Introduction and Objectives</h3> Mutations in the bone morphogenetic protein type II receptor (BMPR-II) are responsible for majority of cases heritable pulmonary arterial hypertension (PAH). lead to reduced Smad1/5-driven expression inhibitor DNA binding 1 (Id1) loss growth suppressive effects BMPs. The impact existing PAH therapies on BMP signalling is lacking. Because prostacyclin analogues effective treatments clinical PAH, we hypothesised that these agents enhance Smad1/Id1...