Fellows Lecture in Pairs: "Targeting metabolite-driven signalling pathways in the type 2 diabetic heart" and "Defining mechanisms of blood-brain barrier dysfunction in dementia using advanced organ-on-a-chip models”

Associate Professor Lisa Heather: “Targeting metabolite-driven signalling pathways in the type 2 diabetic heart”

Type 2 diabetes is a metabolic disorder that causes complications for many organs throughout the body. The leading cause of mortality in type 2 diabetes is cardiovascular disease, however, the mechanisms linking diabetes to heart failure remain unclear. The heart becomes metabolically abnormal early on in the progression of type 2 diabetes, and our work focuses on understanding the consequences of this deranged metabolism. We investigate the different roles metabolites play within the cell, and how changing the concentrations of metabolites in diseases such as diabetes can influence diverse processes via regulation of metabolite-sensitive signalling pathways. Ultimately, by understanding the processes metabolism controls we can start to unravel the pathophysiology of diabetes, and identify new metabolic targets for therapy.

Lisa Heather Biography:

Lisa Heather is an Associate Professor and British Heart Foundation Fellow at the University of Oxford. She completed an undergraduate degree in Medical Biochemistry at the University of Surrey. She studied for her DPhil at the Department of Physiology, Anatomy and Genetics at the University of Oxford, investigating the effects of heart failure on cardiac substrate metabolism.

Lisa was awarded a RD Lawrence Early Career Fellowship by Diabetes UK in 2011, followed by a British Heart Foundation Basic Science Intermediate Fellowship in 2018. Her research group studies cardiac metabolic dysfunction in type 2 diabetes. Her current research focuses on the signalling roles metabolites play within the heart, and how these signalling pathways become dysfunction in type 2 diabetic heart. She was the recipient of the Innovators in Diabetes Award in 2012, Lilly Diabetes Award in 2013 and the Bayliss-Starling Award from the Physiological Society in 2016.

Dr Mootaz Salman: “Defining mechanisms of blood-brain barrier dysfunction in dementia using advanced organ-on-a-chip models”

Dementia is a multifactorial and heterogeneous condition and leading cause of morbidity and mortality. My work aims to answer the question: how does inflammation-mediated blood-brain barrier (BBB) dysfunction lead to the development of dementia? Increasing evidence supports the involvement of BBB dysfunction in neurodegenerative disorders including Parkinson’s and Alzheimer’s; it is evident that this dysfunction happens even before the onset of dementia. In-depth understanding of the cell-cell interactions and signalling pathways between the core elements of the BBB will help in defining therapeutic targets for the prevention of dementia. In my previous work, I identified a number of molecular targets that contribute to barrier integrity function in astrocytes and pericytes and developed microfluidic BBB-on-a-chip models. I will build on this expertise and establish advanced models using patient-derived iPSC lines in order to investigate the role of glymphatic system under mechanobiological factors and determine how biophysical factors such as blood pressure, flow rate and heartbeat control brain waste clearance. My work will provide new tools to understand lifelong brain health, describe the basis of BBB dysfunction in the occurrence and development of dementia, and provide a platform to develop new treatments for neurodegeneration.

Mootaz Salman Biography:

Mootaz graduated as a Clinical Pharmacist before winning two international scholarships for his UK-based MSc and PhD studies investigating the mechanisms of brain water transport where he discovered a novel pharmacological framework for developing drugs to treat traumatic CNS injuries and stroke. This project was a success and one of its exciting outcomes is a drug candidate that will start phase I/II human clinical trial for traumatic brain injury this year.

Mootaz then secured his first postdoctoral fellowship at Harvard Medical School and Boston Children’s Hospital working with Professor Tom Kirchhausen. In this work, he applied microfluidic engineering, advanced imaging and cell biology to develop the world-first in vitro 3D microvessel-on-a-chip platform that can be used for multiple high-resolution dynamic and microscopic imaging modalities. He used this platform to identify the transport mechanism of the recently FDA-approved drug aducanumab in collaboration with Biogen. (Aducanumab is the first approved drug that attempts to treat a possible cause of Alzheimer’s disease in 20 years).

Mootaz has joined DPAG in late 2020. As part of the Wade-Martins group, he is working on developing novel therapeutic targets and new treatments for Parkinson’s using CRISPR/Cas9 of physiologically-relevant human patient-derived iPSC lines.

Mootaz have published 20 articles in 7 years,13 as sole/joint first author and 6 as corresponding author. He holds 2 grants as PI, and awarded another as Co-PI during his time in Boston, won 3 major prizes and established significant industrial collaborations (Biogen, GSK and Mimetas). He’s an Associate Editor for 4 journals and ad hoc reviewer for more than 50 others. Within DPAG, he is appointed as a senior doctoral training advisor (SDTA) and a member of graduate studies, and outreach and public engagement committees.

In recognition of his outstanding work at a critical stage of his career, Mootaz has recently been awarded the prestigious Leverhulme Early Career Fellowship to establish his own independent program of research in close collaboration with the Wade-Martins group where he will be investigating the mechanisms of BBB dysfunction in dementia using advanced 3D mechanobiologial organ-on-a-chip models (which is the title of his talk today where he will present some of his unpublished data and discuss future plans).