As a chief investigator over the last 3-4 years, my research programme is focused on identifying novel biomarkers and disease mechanisms associated with aberrant angiogenesis, inflammation, endothelial dysfunction, stem cell signalling, oxidative stress, and metabolic dysfunction in cardiovascular disease, diabetes and pre-eclampsia.
I am a passionate teacher and educator having contributing to creating, delivering and organising educational material for pharmacy, medicine, nursing, biomedical sciences and biotechnology undergraduate and postgraduate courses.
At UTS, I continued teaching in cardiovascular medicine as well as developing a new subject within the Bachelor of Biotechnology course, Medical Biotechnology, utilizing my clinical, research and industry experience.
Having completed a Master of Pharmacy at King’s College London, I undertook extensive clinical training as a resident pharmacist at the Imperial College Healthcare Trust in London for 3 years. During this time I completed a Certificate in Clinical Pharmacy before progressing onto a Senior Clinical Pharmacist position at the largest private hospital as part of the HCA Healthcare group providing pharmaceutical coronary care. As part of my further clinical training I also completed a Diploma in Clinical Pharmacy and became a tutor for the postgraduate distance learning programme in Clinical Pharmacy with Queen’s University Belfast (QUB) for 7 years.
Following my clinical training, I completed a PhD in molecular biology at the School of Pharmacy at QUB with Prof. Tracy Robson. My PhD and postdoctoral research at QUB led to the discovery of a new clinical utility of a novel anti-angiogenic protein, FKBPL, which targets cancer stem cells. A clinical therapeutic peptide based on its active anti-angiogenic domain, developed by Almac Discovery, has successfully completed Phase Ia clinical trials for the treatment of solid tumours.
I also have significant experience in the translation of research findings including: (i) the development of the new FKBPL-based anti-angiogenic agent (AD-01/ALM201) for the treatment of cancer, (ii) identification and commercialisation of novel biomarkers for early prediction and diagnosis of pre-eclampsia which are patented (WO2018051125A1) and (iii) a spin-out company based on a digital monitoring system for high-risk pregnancies (MiCARE Technologies). At UTS, I am currently funded and mentored through the commercialisation SPARK Sydney program which aims to develop novel and improved monitoring strategies for high-risk pregnancies. Development of home monitoring systems and point of care tests based on established and novel biomarkers is also an area of my research interest facilitated through the collaboration with other academics and clinicians.
Gender equality and women empowerment in academia is my passion, which has led me to get involved with the Academic Women in Science (AWiS) group which I am currently leading. This group facilitiates training, seminars and networking leading to upskilling, confidence and career building of the AWiS members.
The Australian Society for Medical Research
Cardiovascular Research Network (CVRN)
SPHERE: Diabetes Obesity and Metabolic Syndrome CAG Executive Committee; Cardiac and Vascular Disease CAG; Maternal, Newborn & Women's CAG.
International Society for Heart Research (Australasian Section)
Australian Vascular Biology Society
Irish Endocrine Society
European Association for the Study of Diabetes
Pharmaceutical Society of Northern Ireland (2010-2018)
Can supervise: YES
Disease areas of interest: Pre-eclampsia, Cardiovascular disease, Diabetes and Gestational diabetes
- Placental development/myocardial health
- Blood-based and tissue-based biomarkers (miRNA, circRNA, RNA, proteins)
- Identification of disease mechanisms and targets
- Stem cells biology and treatment (mesenchymal stem cells, cancer stem cells)
- Transcriptomics and proteomics
- Endothelial dysfunction/angiogenesis
- Oxidative stress/anti-oxidants
Other areas of research in the same disease areas:
Home monitoring/connected health
- Meta-analysis/systematic reviews
- Service evaluations
- Service development
- Health inequalities
- Global health.
Diabetes and Cardiovascular Disease
Annett, S, Moore, G, Short, A, Marshall, A, McCrudden, C, Yakkundi, A, Das, S, McCluggage, WG, Nelson, L, Harley, I, Moustafa, N, Kennedy, CJ, deFazio, A, Brand, A, Sharma, R, Brennan, D, O'Toole, S, O'Leary, J, Bates, M, O'Riain, C, O'Connor, D, Furlong, F, McCarthy, H, Kissenpfennig, A, McClements, L & Robson, T 2020, 'FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer.', British Journal of Cancer.View/Download from: UTS OPUS or Publisher's site
BACKGROUND:ALM201 is a therapeutic peptide derived from FKBPL that has previously undergone preclinical and clinical development for oncology indications and has completed a Phase 1a clinical trial in ovarian cancer patients and other advanced solid tumours. METHODS:In vitro, cancer stem cell (CSC) assays in a range of HGSOC cell lines and patient samples, and in vivo tumour initiation, growth delay and limiting dilution assays, were utilised. Mechanisms were determined by using immunohistochemistry, ELISA, qRT-PCR, RNAseq and western blotting. Endogenous FKBPL protein levels were evaluated using tissue microarrays (TMA). RESULTS:ALM201 reduced CSCs in cell lines and primary samples by inducing differentiation. ALM201 treatment of highly vascularised Kuramochi xenografts resulted in tumour growth delay by disruption of angiogenesis and a ten-fold decrease in the CSC population. In contrast, ALM201 failed to elicit a strong antitumour response in non-vascularised OVCAR3 xenografts, due to high levels of IL-6 and vasculogenic mimicry. High endogenous tumour expression of FKBPL was associated with an increased progression-free interval, supporting the protective role of FKBPL in HGSOC. CONCLUSION:FKBPL-based therapy can (i) dually target angiogenesis and CSCs, (ii) target the CD44/STAT3 pathway in tumours and (iii) is effective in highly vascularised HGSOC tumours with low levels of IL-6.
Alqudah, A, McMullan, P, Todd, A, O'Doherty, C, McVey, A, McConnell, M, O'Donoghue, J, Gallagher, J, Watson, CJ & McClements, L 2019, 'Service evaluation of diabetes management during pregnancy in a regional maternity hospital: potential scope for increased self-management and remote patient monitoring through mHealth solutions.', BMC health services research, vol. 19, no. 1.View/Download from: UTS OPUS or Publisher's site
BACKGROUND:Pre-gestational and gestational diabetes mellitus are common complications in pregnancy affecting one in six pregnancies. The maternity services are under significant strain managing the increasing number of complex pregnancies. This has an impact on patients' experience of antenatal care. Therefore, there is a clear need to address pregnancy care. One possible solution is to use home-based digital technology to reduce clinic visits and improve clinical monitoring. METHODS:The aim of this study was to evaluate the antenatal services provided to pregnant women with diabetes who were monitored at the joint metabolic and obstetric clinic at the Southern Health and Social Care Trust in Northern Ireland. RESULTS:The questionnaires were completed by sixty-three women, most of whom had gestational diabetes mellitus. Most of the participants were between 25 and 35 years of age (69.8%), had one or more children (65.1%) and spent over 2 h attending the clinics (63.9%); 78% of women indicated that their travel time to and from the clinic appointment was over 15 min. Over 70% of women used smartphones for health-related purposes. However, only 8.8% used smartphones to manage their health or diabetes. Less than 25% of the women surveyed expressed concerns about using digital technology from home to monitor various aspects of their health in pregnancy. CONCLUSIONS:Overall, pregnant women who had or developed diabetes in pregnancy experience frequent hospital visits and long waiting times in the maternity clinics. Most of these pregnant women are willing to self-manage their condition from home and to be monitored remotely by the healthcare staff.
Andrejic, OM, Vucic, RM, Pavlovic, M, McClements, L, Stokanovic, D, Jevtovic-Stoimenov, T & Nikolic, VN 2019, 'Association between Galectin-3 levels within central and peripheral venous blood, and adverse left ventricular remodelling after first acute myocardial infarction', SCIENTIFIC REPORTS, vol. 9.View/Download from: UTS OPUS or Publisher's site
Fergie, N, Todd, N, McClements, L, McAuley, D, O’Kane, C & Krasnodembskaya, A 2019, 'Hypercapnic acidosis induces mitochondrial dysfunction and impairs the ability of mesenchymal stem cells to promote distal lung epithelial repair', The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, vol. 33, pp. 5585-5598.View/Download from: UTS OPUS or Publisher's site
Jerotic, D, Matic, M, Suvakov, S, Vucicevic, K, Damjanovic, T, Savic-Radojevic, A, Pljesa-Ercegovac, M, Coric, V, Stefanovic, A, Ivanisevic, J, Jelic-Ivanovic, Z, McClements, L, Dimkovic, N & Simic, T 2019, 'Association of Nrf2, SOD2 and GPX1 Polymorphisms with Biomarkers of Oxidative Distress and Survival in End-Stage Renal Disease Patients', TOXINS, vol. 11, no. 7.View/Download from: UTS OPUS or Publisher's site
Lopez-Campos, G, Bonner, E & McClements, L 2019, 'An Integrative Biomedical Informatics Approach to Elucidate the Similarities Between Pre-Eclampsia and Hypertension', Studies in Health Technology and Informatics, vol. 264, pp. 988-992.View/Download from: UTS OPUS or Publisher's site
Pre-eclampsia is a pregnancy condition affecting 5-10% of pregnancies, and it is the leading cause of death in pregnancy associated with increased risk of cardiovascular disease later in life. Despite research, the pathogenesis of pre-eclampsia is still poorly understood. In this paper, we investigate the overlapping pathogenic mechanisms between pre-eclampsia and adult hypertension using an integrative biomedical informatics strategy that combined text mining techniques to identify genes and proteins, with geneset analyses, generating knowledge on the pathways and mechanisms involved in these conditions. We identified several overlapping pathogenic pathways/systems including metabolic pathways, developmental biology pathways, immune system, haemostasis, tyrosine kinase pathways, extracellular matrix and oxidative stress pathways. This bioinformatics approach could be applied for investigating mechanistic pathways of other disorders.
McClements, L, Annett, S, Yakkundi, A, O'Rourke, M, Valentine, A, Moustafa, N, Alqudah, A, Simões, BM, Furlong, F, Short, A, McIntosh, SA, McCarthy, HO, Clarke, RB & Robson, T 2019, 'FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4.', BMC cancer, vol. 19, no. 1.View/Download from: UTS OPUS or Publisher's site
BACKGROUND:Optimising breast cancer treatment remains a challenge. Resistance to therapy is a major problem in both ER- and ER+ breast cancer. Tumour recurrence after chemotherapy and/or targeted therapy leads to more aggressive tumours with enhanced metastatic ability. Self-renewing cancer stem cells (CSCs) have been implicated in treatment resistance, recurrence and the development of metastatic disease. METHODS:In this study, we utilised in vitro, in vivo and ex vivo breast cancer models using ER+ MCF-7 and ER- MDA-MB-231 cells, as well as solid and metastatic breast cancer patient samples, to interrogate the effects of FKBPL and its peptide therapeutics on metastasis, endocrine therapy resistant CSCs and DLL4 and Notch4 expression. The effects of FKBPL overexpression or peptide treatment were assessed using a t-test or one-way ANOVA with Dunnett's multiple comparison test. RESULTS:We demonstrated that FKBPL overexpression or treatment with FKBPL-based therapeutics (AD-01, pre-clinical peptide /ALM201, clinical peptide) inhibit i) CSCs in both ER+ and ER- breast cancer, ii) cancer metastasis in a triple negative breast cancer metastasis model and iii) endocrine therapy resistant CSCs in ER+ breast cancer, via modulation of the DLL4 and Notch4 protein and/or mRNA expression. AD-01 was effective at reducing triple negative MDA-MB-231 breast cancer cell migration (n ≥ 3, p < 0.05) and invasion (n ≥ 3, p < 0.001) and this was translated in vivo where AD-01 inhibited breast cancer metastasis in MDA-MB-231-lucD3H1 in vivo model (p < 0.05). In ER+ MCF-7 cells and primary breast tumour samples, we demonstrated that ALM201 inhibits endocrine therapy resistant mammospheres, representative of CSC content (n ≥ 3, p < 0.05). Whilst an in vivo limiting dilution assay, using SCID mice, demonstrated that ALM201 alone or in combination with tamoxifen was very effective at delaying tumour recurrence by 12 (p < 0.05) or 21 days (p < 0.001), respectively, by reducing the number o...
Smyth, L, McClements, L & Murphy, P 2019, 'Engaging hard-to-reach populations in research on health in pregnancy: the value of Boal’s simultaneous dramaturgy', Arts and Health: An International Journal for Research, Policy and Practice.View/Download from: UTS OPUS or Publisher's site
Background: Migrant populations are among the hardest to reach for research purposes.
Methods: An interdisciplinary research team piloted a modified version of Boal's simultaneous dramaturgy with Roma mothers in Belfast.
Results: The technique, based on scripted performances, translations, and discussions, proved effective for engaging with this hard-to-reach population, despite low levels of literacy, high language barriers, and cultural separateness. The approach uncovered attitudes to pregnancy which reinforce health inequalities, and present significant challenges for improving the health of marginalized populations.
Conclusions: This pilot underlines the importance of building trust through holistic approaches to working with hard-to-reach populations through the creative arts.
Suvakov, S, Jerotic, D, Damjanovic, T, Milic, N, Pekmezovic, T, Djukic, T, Jelic-Ivanovic, Z, Savic Radojevic, A, Pljesa-Ercegovac, M, Matic, M, McClements, L, Dimkovic, N, Garovic, VD, Albright, RC & Simic, T 2019, 'Markers of Oxidative Stress and Endothelial Dysfunction Predict Haemodialysis Patients Survival.', American journal of nephrology, vol. 50, no. 2, pp. 115-125.View/Download from: Publisher's site
INTRODUCTION:Overall survival of patients with end-stage renal disease (ESRD) remains poor. Oxidative stress is one of the major risk factors associated with mortality in this patient group. As glutathione S-transferases (GST) are well-established antioxidants, we hypothesized that a model including GST gene polymorphisms, oxidative damage byproducts and cell adhesion markers has a prognostic role in ESRD patient survival. METHODS:A prospective study of 199 patients with ESRD on haemodialysis was conducted. GST genotype, oxidative stress byproducts and cell adhesion molecules were measured in plasma. Multivariate Cox regression and Kaplan-Meier survival analyses were performed to test the predictive ability of these parameters in the 8-year follow-up period. RESULTS:GSTM1-null genotype was associated with significantly shorter overall (HR 1.6, p = 0.018) and cardiovascular-specific (HR 2.1, p = 0.010) survival. Oxidative stress byproducts (advanced oxidation protein products [AOPP], prooxidant-antioxidant balance [PAB], malondialdehyde [MDA]) and cell adhesion molecules (soluble vascular cell adhesion molecule-1 [sVCAM-1] and soluble intercellular adhesion molecule-1 [sICAM-1]) demonstrated a significant predictive role in terms of overall and cardiovascular survival. When 6 biomarkers (GSTM1 genotype, high AOPP/PAB/MDA/-sVCAM-1/sICAM-1) were combined into a scoring model, a significantly shorter overall and cardiovascular survival was observed for patients with the highest score (p < 0.001). CONCLUSION:We identified a novel panel of biomarkers that can be utilized in predicting survival in ESRD patients. This biomarker signature could enable better monitoring of patients and stratification into appropriate treatment groups.
Alqudah, A, McKinley, MC, McNally, R, Graham, U, Watson, CJ, Lyons, TJ & McClements, L 2018, 'Risk of pre-eclampsia in women taking metformin: a systematic review and meta-analysis.', Diabetic medicine : a journal of the British Diabetic Association, vol. 35, no. 2, pp. 160-172.View/Download from: UTS OPUS or Publisher's site
AIMS:To perform meta-analyses of studies evaluating the risk of pre-eclampsia in high-risk insulin-resistant women taking metformin prior to, or during pregnancy. METHODS:A search was conducted of the Medline, EMBASE, Web of Science and Scopus databases. Both randomized controlled trials and prospective observational cohort studies of metformin treatment vs. placebo/control or insulin either prior to or during pregnancy were selected. The main outcome measure was the incidence of pre-eclampsia in each treatment group. RESULTS:Overall, in five randomized controlled trials comparing metformin treatment (n = 611) with placebo/control (n = 609), no difference in the risk of pre-eclampsia was found [combined/pooled risk ratio (RR), 0.86 (95% CI 0.33-2.26); P = 0.76; I2 = 66%]. Meta-analysis of four cohort studies again showed no significant effect [RR, 1.21 (95% CI 0.56-2.61); P = 0.62; I2 = 30%]. A meta-analysis of eight randomized controlled trials comparing metformin (n = 838) with insulin (n = 836), however, showed a reduced risk of pre-eclampsia with metformin [RR, 0.68 (95% CI 0.48-0.95); P = 0.02; I2 = 0%]. No heterogeneity was present in the metformin vs. insulin analysis of randomized controlled trials, whereas high levels of heterogeneity were present in studies comparing metformin with placebo/control. Pre-eclampsia was a secondary outcome in most of the studies. The mean weight gain from time of enrolment to delivery was lower in the metformin group (P = 0.05, metformin vs. placebo; P = 0.004, metformin vs. insulin). CONCLUSIONS:In studies randomizing pregnant women to glucose-lowering therapy, metformin was associated with lower gestational weight gain and a lower risk of pre-eclampsia compared with insulin.
McNally, R, Alqudah, A, Obradovic, D & McClements, L 2017, 'Elucidating the Pathogenesis of Pre-eclampsia Using In Vitro Models of Spiral Uterine Artery Remodelling.', Current hypertension reports, vol. 19, no. 11, pp. 93-93.View/Download from: UTS OPUS or Publisher's site
The aim of the study is to perform a critical assessment of in vitro models of pre-eclampsia using complementary human and cell line-based studies. Molecular mechanisms involved in spiral uterine artery (SUA) remodelling and trophoblast functionality will also be discussed.A number of proteins and microRNAs have been implicated as key in SUA remodelling, which could be explored as early biomarkers or therapeutic targets for prevention of pre-eclampsia. Various 2D and 3D in vitro models involving trophoblast cells, endothelial cells, immune cells and placental tissue were discussed to elucidate the pathogenesis of pre-eclampsia. Nevertheless, pre-eclampsia is a multifactorial disease, and the mechanisms involved in its pathogenesis are complex and still largely unknown. Further studies are required to provide better understanding of the key processes leading to inappropriate placental development which is the root cause of pre-eclampsia. This new knowledge could identify novel biomarkers and treatment strategies.
McClements, L, Annett, S, Yakkundi, A & Robson, T 2016, 'The Role of Peptidyl Prolyl Isomerases in Ageing and Vascular Diseases', CURRENT MOLECULAR PHARMACOLOGY, vol. 9, no. 2, pp. 165-179.View/Download from: Publisher's site
Bennett, R, Yakkundi, A, McKeen, HD, McClements, L, McKeogh, TJ, McCrudden, CM, Arthur, K, Robson, T & McCarthy, HO 2015, 'RALA-mediated delivery of FKBPL nucleic acid therapeutics', NANOMEDICINE, vol. 10, no. 19, pp. 2989-3001.View/Download from: Publisher's site
Nelson, L, McKeen, HD, Marshall, A, Mulrane, L, Starczynski, J, Storr, SJ, Lanigan, F, Byrne, C, Arthur, K, Hegarty, S, Ali, AA, Furlong, F, McCarthy, HO, Ellis, IO, Green, AR, Rakha, E, Young, L, Kunkler, I, Thomas, J, Jack, W, Cameron, D, Jirstrom, K, Yakkundi, A, McClements, L, Martin, SG, Gallagher, WM, Dunn, J, Bartlett, J, O'Connor, D & Robson, T 2015, 'FKBPL: a marker of good prognosis in breast cancer', ONCOTARGET, vol. 6, no. 14, pp. 12209-12223.View/Download from: UTS OPUS or Publisher's site
Yakkundi, A, Bennett, R, Hernandez-Negrete, I, Delalande, J-M, Hanna, M, Lyubomska, O, Arthur, K, Short, A, McKeen, H, Nelson, L, McCrudden, CM, McNally, R, McClements, L, McCarthy, HO, Burns, AJ, Bicknell, R, Kissenpfennig, A & Robson, T 2015, 'FKBPL Is a Critical Antiangiogenic Regulator of Developmental and Pathological Angiogenesis', ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, vol. 35, no. 4, pp. 845-854.View/Download from: UTS OPUS or Publisher's site
Donley, C, McClelland, K, McKeen, HD, Nelson, L, Yakkundi, A, Jithesh, PV, Burrows, J, McClements, L, Valentine, A, Prise, KM, McCarthy, HO & Robson, T 2014, 'Identification of RBCK1 as a novel regulator of FKBPL: implications for tumor growth and response to tamoxifen', ONCOGENE, vol. 33, no. 26, pp. 3441-3450.View/Download from: Publisher's site
McClements, L, Yakkundi, A, Papaspyropoulos, A, Harrison, H, Ablett, MP, Jithesh, PV, McKeen, HD, Bennett, R, Donley, C, Kissenpfennig, A, McIntosh, S, McCarthy, HO, O'Neill, E, Clarke, RB & Robson, T 2013, 'Targeting Treatment-Resistant Breast Cancer Stem Cells with FKBPL and Its Peptide Derivative, AD-01, via the CD44 Pathway', CLINICAL CANCER RESEARCH, vol. 19, no. 14, pp. 3881-3893.View/Download from: Publisher's site
Yakkundi, A, McCallum, L, O'Kane, A, Dyer, H, Worthington, J, McKeen, HD, McClements, L, Elliott, C, McCarthy, HO, Hirst, DG & Robson, T 2013, 'The Anti-Migratory Effects of FKBPL and Its Peptide Derivative, AD-01: Regulation of CD44 and the Cytoskeletal Pathway', PLOS ONE, vol. 8, no. 2.View/Download from: UTS OPUS or Publisher's site
Alqudah, A, McNally, R, Todd, N, Edgar, K, Short, A, Grieve, D, Robson, T & McClements, L 2018, 'Downregulation of FKBPL influences metabolic and vascular function in experimental model of diabetes', Diabetologia, EASD Annual Meeting of the European Association for the Study of Diabetes, Springer Verlag, Berlin, Germany.View/Download from: Publisher's site
Background and aims: There are currently over 400 million people
living with diabetes in the world. Cardiovascular disease (CVD) is the
leading cause of death globally and people with diabetes have a three-fold
higher incidence of CVD. The underlying mechanisms implicated in the
development of CVD in association with diabetes are linked to aberrant
angiogenesis and endothelial dysfunction. FKBPL is a novel antiangiogenic protein which has a critical role in physiological and pathological angiogenesis. While Fkbpl homozygous knockout mice resulted
in embryonic lethality, Fkbpl+/− embryos were viable and developed
normally but showed signs of early vascular dysfunction and leakiness.
Based on these findings, we now investigate the effect of FKBPL downregulation on metabolic and vascular function in a streptozotocin (STZ)-
induced diabetic mouse model.
Materials and methods: Both wild-type (WT, C57BL/6N) Fkbpl+/+ and
Fkbpl+/− mice were randomized between 10 and 12 weeks of age to either
STZ treatment (5 consecutive STZ injections at 50 mg/kg/day) or vehicle
control treatment with citrate buffer. Metabolic parameters were measured weekly. Insulin tolerance (ITT) and echocardiography tests were
performed at 12 weeks of diabetes. Following 13 weeks of diabetes,
organs were excised for immunofluorescent ex-vivo analysis.
Comparisons were analyzed using one-way ANOVA.
Results: Blood glucose levels were higher in Fkbpl+/− diabetic mice
compared to Fkbpl+/+ diabetic controls during a period of 8 to 12 weeks
of diabetes (p < 0.05, n ≥ 6). Glycated haemoglobin (HbA1c) was higher
in both non-diabetic and diabetic Fkbpl+/− mice compared to Fkbpl+/+
controls (non-diabetic, 31 ± 0.9 mmol/mol vs. 27.25 ± 0.8 mmol/mol, p <
0.05, n ≥ 6; diabetic, 88.7 ± 3.1 mmol/mol vs. 69.8 ± 3.5 mmol/mol, p <
0.001, n ≥ 6). Notably, Fkbpl+/− non-diabetic mice gained more weight
compared to Fkbpl+/+ non-diabetic controls on a normal diet (10.92 ±
0.51 g vs. 7.05 ± 1.02 g, p < 0.05, n ≥ 6). However...
Alqudah, A, McNally, R, Todd, N, Grieve, D, Robson, T & McClements, L 2018, 'The role of a novel anti-angiogenic protein, FKBPL, in angiogenesis associated with cardiac dysfunction', Heart, The Scottish Cardiovascular Forum 2018, BMJ Publishing Group.
People with diabetes have a five-fold higher incidence of cardiovascular disease, the leading cause of death globally. FKBPL is a novel angiogenesis-related protein, with a critical role in physiological and pathological angiogenesis. A first-in-class clinical FKBPL peptide mimetic, ALM201, has successfully completed clinical trials for treatment of solid tumours. FKBPL haploinsufficient (Fkbpl± ) mice, have a pro-angiogenic phenotype, accompanied by vascular dysfunction. Vascular dysfunction is associated with CVD and T2D.
In view of these findings, we now investigate a specific role for FKBPL in angiogenesis associated with cardiac dysfunction. In streptozotocin (STZ)-induced diabetic mice (50 mg/kg i.p. for 5 consecutive days), cardiac FKBPL mRNA levels were downregulated at 12 weeks compared to vehicle controls (p<0.05, n=5); this was associated with diastolic dysfunction (e.g. mitral valve E/A ratio). Similarly, in an experimental mouse model of myocardial infarction (MI) associated with severe cardiac ischaemia/hypoxia and increased angiogenesis, FKBPL mRNA (p<0.05) and protein levels (p<0.01) were downregulated versus sham controls (n≥3). Complementary in vitro studies using human umbilical vein endothelial cells (HUVEC) demonstrated increased migration and differentiation following 24 hour exposure to hypoxia (1%) when compared to normoxia (p<0.01, n=6). In addition, FKBPL protein levels were downregulated following exposure to hypoxia (p<0.01, n=6), whilst activation of HIF-1α in normoxia by 24 hour DMOG treatment led to a two-fold reduction in FKBPL protein levels (p<0.01, n=3). Furthermore, HUVEC exposed to high glucose (30 mM for 24 hour) demonstrated downregulation of FKBPL compared to osmotic control (p<0.05, n=3). Interestingly, fenofibrate (50 µM) treatment was able to restore HUVEC levels of FKBPL in hypoxia (p<0.01, n=3). In conclusion, FKBPL may serve a key regulatory role in pathological angiogenesis associated with cardiac dysfunction and, a...
Annett, S, Moore, G, Short, A, Moustafa, N, Das, S, O'Connor, D, McCrudden, C, Kissenpfenning, A, Nelson, L, Harley, I, Arthur, K, Yakkundi, A, McCluggage, G, Marshall, A, Furlong, F, McCarthy, HO, Cotton, G, Harrison, T, McClements, L & Robson, T 2018, 'FKBPL as a novel therapeutic target and prognostic biomarker in high grade serous ovarian cancer', CANCER RESEARCH, Annual Meeting of the American-Association-for-Cancer-Research (AACR), AMER ASSOC CANCER RESEARCH, Chicago, IL.View/Download from: Publisher's site
McNally, R, Todd, N, Alqudah, A, Robson, T, Grieve, D & McClements, L 2018, 'The role of a novel angiogenesis related protein, FKBPL, in spiral uterine artery remodelling important for the pathogenesis of preeclampsia', Heart, The Scottish Cardiovascular Forum 2018, BMJ Publishing Group.
Introduction Preeclampsia is a complication which occurs in 5%–6% of pregnancies, characterised by high blood pressure and/or other organ dysfunction in the third trimester of pregnancy. Preeclampsia has short-term risks for the mother and child, but is also associated with remote cardiovascular disease and/or type 2 diabetes mellitus in both. The pathogenesis of preeclampsia is unclear but it appears to be attributed to inappropriate remodelling of spiral uterine artery as a result of dysregulated trophoblast function. We investigated the involvement of novel regulator of developmental and pathological angiogenesis, FKBPL, and its role in the pathophysiology of preeclampsia.
Methods Trophoblast cells (HTR8.SV.neo, BeWo and JAR) were exposed to hypoxic (1%) or normoxic (21%) conditions before wound scratch migration assays were performed, and FKBPL protein levels measured. BeWo cells were treated with the HIF-1α activator, DMOG, for 24 hour before protein lysates were extracted for western blotting analysis. Colony forming efficiency and the number of holoclones, meroclones and paraclones of both HTR8.SV.neo and JAR trophoblast cells were determined in the presence of hypoxia or normoxia via clonogenic assay.
Results BeWo and JAR migration increased by approximately 40% following 24 hour exposure to hypoxia (n=6; BeWo, p<0.05; JAR, p<0.01), and FKBPL protein expression was downregulated (n=3; HTR8.SV.neo, p<0.01; BeWo, p<0.05; JAR, p<0.01), when compared to normoxia. DMOG treatment downregulated FKBPL protein levels in BeWo cells (n=3, p<0.01). JAR colony formation was reduced by approximately 70% in hypoxia (n=3, p<0.01); all colonies appeared to be holoclones. No change in colony formation was observed in HTR8.SV.neo cells; however, there was over two-fold reduction of holoclones, and an increase in differentiated colonies, meroclones plus paraclones (n=3, p<0.05).
Conclusion Our in vitro data suggest that FKBPL plays an important role in trophoblast functio...
Todd, N, McNally, R, Alqudah, A, Krasnodembskaya, A & McClements, L 2018, 'MESENCHYMAL STEM CELLS INFLUENCE TROPHOBLAST AND ENDOTHELIAL CELL FUNCTIONALITY IMPORTANT FOR PREVENTION OF PRE-ECLAMPSIA VIA A NOVEL ANTI-ANGIOGENIC PROTEIN, FKBPL', European Meeting on Hypertension and Cardiovascular Protection, Barcelona, Spain.View/Download from: Publisher's site
Objective: Pre-eclampsia is a disorder affecting 5–6% of all pregnancies globally. It is characterised by the new onset of hypertension and proteinuria post 20 weeks gestation. Pre-eclampsia is a leading cause of morbidity and mortality in both mothers and children. Although the pathogenesis of pre-eclampsia is poorly understood, aberrant angiogenesis and inadequate trophoblast cell function have both been implicated. Mesenchymal Stem Cell (MSC)-based therapies have shown benefits in animal models of pre-eclampsia however, the underlying mechanisms are not well understood. FKBPL is a novel anti-angiogenic protein which has a critical role in developmental, physiological and pathological angiogenesis. In this study, our objective was to evaluate the effects of MSC–conditioned medium (MSC-CM) on migration and differentiation of trophoblast and endothelial cell lines under both normoxic and hypoxic conditions. The role of FKBPL signalling in these processes was also investigated.
Design and method: Human trophoblast (BeWo and Jar) and endothelial cells (HUVEC) were incubated in the presence of human bone marrow- derived MSC-CM, normal or serum free medium under normoxia (21% oxygen) or hypoxia (1% oxygen). The confluent cell monolayer was wounded and the percentage of wound closure assessed at 24 h. HUVEC were stained with Calcein prior to 6-hour incubation in the presence of MSC-CM, normal or serum free medium under normoxia or hypoxia. Tubule formation was assessed using Image J. FKBPL protein expression was evaluated using western blot analysis where cells were lysed in RIPA buffer before being subjected to western blotting and probed for FKBPL and GAPDH.
Results: MSC-CM promoted cell migration significantly in all three cell lines under both normoxia and hypoxia compared to normal medium (n = 6; p < 0.001). MSC-CM also significantly increased the formation of HUVEC tubule networks under both normoxia and hypoxia compared to normal medium. Furthermore, concomit...
Alqudah, A, McNally, R, Connell, A, Lyons, T, Grieve, D, Robson, T & McClements, L 2017, 'FKBPL, a novel angiogenesis-related protein, is downregulated in response to myocardial stress', Irish Journal of Medical Science, Springer Verlag.
People with diabetes show five-fold higher incidence of cardiovascular disease,
the leading causes of death globally. FKBPL is a novel angiogenesisrelated
protein, with a critical role in physiological and pathological angiogenesis.
A first-in-class clinical FKBPL peptide mimetic, ALM201, is currently
in phase I/II clinical trials for treatment of solid tumours. More recently,
in FKBPL knockdown (FKBPL+/-) mice, a pro-angiogenic phenotype
was observed, accompanied by vascular dysfunction and a propensity to
become overweight and glucose intolerant when fed a high fat diet. We
now investigate a specific role for FKBPL in myocardial angiogenesis associated
with diabetes. In streptozotocin (STZ) mice, cardiac FKBPL mRNA
levels were significantly downregulated at 12 weeks post STZ injection
versus vehicle controls (p<0.05, n=5), in association with diastolic dysfunction
(e.g. mitral valve E/A ratio). This was in concert with a reduction of
FKBPL protein in hearts from STZ-induced vs. control diabetic rats (p<0.01,
n=3), also at 12 weeks. Complementary in vitro studies in cultured endothelial
cells (HUVEC) demonstrated two-fold reduction in FKBPL protein
levels following exposure to hypoxia (1%) for 24 h (p<0.01, n=6), indicating
that reduced FKBPL levels observed in vivo may be, at least in part, driven
by impaired oxygenation. Indeed, in an experimental mouse model of myocardial
infarction (MI), associated with severe cardiac ischaemia/hypoxia and
increased angiogenesis, FKBPL mRNA (p<0.05) and protein levels
(p<0.01) were downregulated versus sham controls (n≥3). In conclusion,
FKBPL may be a key early regulator of cardiac angiogenesis in diabetes,
and may thereby hold novel biomarker and therapeutic potential.
McClements, L, McNally, R, Alqudah, A, Robson, T, Watson, C & Lyons, T 2017, 'Elucidating the role of novel angiogenesis-related proteins, FKBPL and SIR-1, in trophoblast cells exposed to diabetic stimuli: potential implications for preeclampsia', Diabetologia, EASD Annual Meeting of the European Association for the Study of Diabetes, Springer Verlag.
Background and aims: Diabetic vascular complications are closely related
to irregular angiogenesis, oxidative stress and lipid peroxidation.
Preeclampsia (PE) is a pregnancy condition characterised by high blood
pressure, proteinuria and multi-organ dysfunction. PE occurs in 4-6% of
pregnancies; however in women with diabetes the incidence of PE is
increased four-fold. Furthermore, PE does not only have short-term risks,
but long-term is associated with cardiovascular disease and/or Type 2
diabetes in both mothers and offspring. Despite research efforts in this
area, currently there are no reliable early biomarkers, preventative or
treatment strategies for PE, other than delivery. Moreover, paucity of
mechanistic data is impeding the development of successful preventative
S430 Diabetologia (2017) 60 (Suppl 1):S1–S608
and curative therapies of PE, particularly in the context of diabetes. The
novel angiogenesis-related protein, FKBPL, is a critical regulator of developmental
and pathological angiogenesis and closely associated with
nutrient-sensing protein, SIRT-1. Therefore, FKBPL may play a key role
in the pathophysiology of PE associated with diabetes.
Materials and methods: Three different trophoblast cells lines
(HTR8.SV.neo, BeWo and Jar) were exposed to diabetic stimuli: normal
vs. high glucose (5.5 vs. 10, 20, 40 mM), native vs. highly oxidised,
glycated low density lipoprotein (N- vs. HOG-LDL; 25 μg protein/ml),
or hypoxia (1%); then FKBPL and SIRT-1 protein expression and mRNA
levels were measured in cell lysates. FKBPL and SIRT-1 were also measured
in placental extracts using western blotting.
Results: FKBPL and SIRT-1 protein expression differed across the three
trophoblast cell lines, with Jar cells expressing the highest levels of
FKBPL and SIRT-1, BeWo cells expressing the lowest level of SIRT-1
and HTR8.SV.neo cells expressing the lowest level of FKBPL. In BeWo
cells treated with high vs. normal glucose (48 h), FKBPL mRNA levels
were increased 1.3-f...
MiCare Technologies, Belfast, UK
The Royal College of Surgeons, Dublin, Ireland
Queen's University Belfast, Northern Ireland, UK
The Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
The Southern Health and Social Care Trust, Craigavon, Northern Ireland, UK
NI Connected Health Innovation Centre (CHIC), The University of Ulster, Jordanstown, UK
Yarra Software, Belfast, UK
The Mayo Clinic, Rochester, US
The Irish Centre for Fetal and Neonatal Translational Research (INFANT), Cork, Ireland
University of Nis. Serbia
University of Belgrade, Serbia
Clinical Centre, Nis, Serbia
The Hashemite University, Jordan