Cardiac and skeletal muscle progenitor cells - driving regeneration ability by tryptophan metabolites

Summary

The School of Biomedical Sciences invites applications from prospective postgraduate researchers who wish to commence study for a PhD in the academic year 2024/25. We especially welcome applications that connect to the School's core research areas, which include the mechanisms underlying diseases causing health problems in an ageing population.

This core research area aligns closely with the research interests of this project’s supervisory team, who are well established in the investigation of the cellular mechanisms underlying diseases of the cardiovascular system - a principal cause of age-related morbidity and mortality.

This project will examine the cellular mechanisms in which metabolic products of the essential amino acid tryptophan can influence repair and regeneration in the heart and skeletal muscle. It will use established techniques in cell culture, isolating cells from tissue samples, with analyses using assays of proteins, gene expression, and assessments of cell viability, structure and function.

The main route for tryptophan metabolism is the kynurenine pathway, so named after a major metabolite that appears early in this pathway. It has been shown that tryptophan metabolism increases after cardiac injury and that interruption of the first step of the kynurenine pathway can impair regeneration of the injured heart (Zhang et al., 2022, Nat. Commun. 13:6371). This was shown to occur via two mechanisms, the formation of new cardiomyocytes and by increased levels of angiogenesis within the myocardium. Both of these are essential to drive repair of functional cardiac tissue: contractility is the essential ability of myocardium and this cannot happen without cardiomyocytes; in addition, these cells have a huge demand for oxygen and nutrients, so any effective contractile tissue will not function without an extensive microvascular network to provide these.

Our current translational research programme in heart failure patients has recently identified that specific drug agents increase levels of kynurenic acid in cardiac tissue, a non-toxic tryptophan metabolite, which indicates shifts in how tryptophan is metabolised dependent on clinical treatment. This finding raises intriguing questions of how these processes may be linked, particularly whether there are responses in the cells of the myocardium to this drug, leading to the processes mentioned previously, of cardiomyogenesis and angiogenesis. In addition to cardiac dysfunction, patients with heart failure have secondary pathology that contributes towards disease progression, such as skeletal muscle dysfunction. We recently identified that tryptophan metabolism in skeletal muscle biopsies of patients with heart failure is disrupted via specific drug agents and this was closely linked to underlying changes in skeletal muscle health related to atrophy and myogenesis. Together, this highlights a potential and important role for the kynurenine pathway in regulating both cardiac and skeletal muscle pathology in health and disease.

These questions are ones which this supervisory team is uniquely set up to investigate, given the work done previously by the project’s lead supervisor in examining the role of kynurenine pathway compounds on neuronal cell viability (Smith et al., 2007, Biochem. Soc. Trans. 35:1287-1289; Smith et al., 2009, Neurotox. Res. 15:303-310; Darlington et al., 2010, Int. J. Tryptophan Res. 3:51-59), followed by extensive work on cardiac progenitor cell physiology and responses to damage (Ellison et al., 2011, J. Am. Coll. Cardiol. 58:977-86; Ellison et al., 2013, Cell 154(4):827-42; Smith et al., 2014 Nat. Prot. 9(7):1662-1681; Smith et al., 2022, Sci. Rep. 12(1):10132). This is in addition to the expertise of the co-supervisor in the mechanisms underlying skeletal muscle pathology and regeneration (Garnham et al., 2020, J. Cachexia Sarcopenia Muscle 11:394-404; Caspi et al., 2020, J. Am. Heart Assoc. 9:e017091; Moriscot et al., 2021, NPJ Regen. Med. 6:17; Gallagher et al., 2023, J. Sport Health Sci. S2095).

The aim of the project will be to identify the impact of kynurenine pathway compounds on properties of cardiac and skeletal muscle progenitor cells (satellite cells). This will be achieved by studying their titrated effects on cell viability, expression of key genes and proteins, and the link to tissue repair and regeneration. This will improve understanding of how tryptophan metabolites can influence striated muscle regeneration. This is an opportunity for a dedicated researcher to join this exciting collaboration to work amongst two unique research groups in order to address an important clinical problem in heart failure.

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree. Applicants are advised to check with the relevant School prior to making an application. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the School or Graduate School prior to making an application.

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.0 overall with at least 5.5 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid. Some schools and faculties have a higher requirement.