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Dr A.J. Smith
Applications accepted all year round
Self-Funded PhD Students Only
About the Project
With the significant and growing healthcare burden caused by chronic heart failure, the ability to develop new directions for treatment, reducing or preventing the worsening of disease, would be of great value. Since the discovery of endogenous cardiac stem cells (eCSCs) by Beltrami et al. in 2003 (Cell 114(6):763-776), followed by definitive evidence of human cardiac renewal throughout life (Bergmann et al. (2009) Science 324(5923):98-102), there has been keen interest in determining what role(s) these cells play in cardiac regeneration and repair.
Much interest to date has focused closely on their ability to form cardiac myocytes, however eCSCs are also capable of generating vascular cell types (endothelial and smooth muscle cells), offering the ability to generate new blood vessels within the heart. However, another important aspect of eCSC biology is their ability to generate and release a powerful ‘secretome’, allowing beneficial impact on cells via paracrine actions. This is believed to be the underlying cause of the significant improvement in heart function seen when eCSCs were delivered in clinical trials to patients, after cardiac damage from heart attack (Hong and Bolli (2014) Curr. Treat. Options Cardiovasc. Med. 16(7):324).
This project will examine the role played by receptor tyrosine kinases (RTKs) on the promotion of eCSC secretome generation, and in governing the ability of eCSCs to form vascular cell lineages. We will also investigate the impact of RTK inhibitors, drugs with known cardiotoxicity, on secretome generation and release.
Much interest to date has focused closely on their ability to form cardiac myocytes, however eCSCs are also capable of generating vascular cell types (endothelial and smooth muscle cells), offering the ability to generate new blood vessels within the heart. However, another important aspect of eCSC biology is their ability to generate and release a powerful ‘secretome’, allowing beneficial impact on cells via paracrine actions. This is believed to be the underlying cause of the significant improvement in heart function seen when eCSCs were delivered in clinical trials to patients, after cardiac damage from heart attack (Hong and Bolli (2014) Curr. Treat. Options Cardiovasc. Med. 16(7):324).
This project will examine the role played by receptor tyrosine kinases (RTKs) on the promotion of eCSC secretome generation, and in governing the ability of eCSCs to form vascular cell lineages. We will also investigate the impact of RTK inhibitors, drugs with known cardiotoxicity, on secretome generation and release.
Funding Notes
The PhD will start when a suitable applicant is selected and funding confirmed. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) or above in a relevant subject. The funding is open to international students (subject to eligibility); self-funded students, or those with funding already available and seeking a suitable research project, are encouraged to apply. For further details, please contact Dr. Smith ([Email Address Removed]).
References
Ellison GM, Vicinanza C, Smith AJ, Aquila I, Leone A, et al. Adult c-kitpos Cardiac Stem Cells Are Necessary and Sufficient for Functional Cardiac Regeneration and Repair. Cell 154(4), 827-42 (2013).
Smith AJ, Lewis FC, Aquila I, Waring CD, Agosti V, et al. Isolation and characterisation of resident endogenous c-kit-positive cardiac stem cells (eCSCs) from the adult mouse and rat heart. Nat. Prot. 9(7): 1662-1681 (2014).
Vicinanza C, Aquila I, Scalise M, Cristiano F, Marino F, Cianflore E, Mancuso T, Marotta P, Sacco W, Lewis FC, Couch L, Shone V, Gritti G, Torella A, Smith AJ, Terracciano CMN, Britti D, Veltri P, Indolfi C, Nadal-Ginard B, Ellison-Hughes GM, Torella D (2017) Adult cardiac stem cells are multipotent and robustly myogenic: c-kit expression is necessary but not sufficient for their identification. Cell Death and Differentiation doi: 10.1038/cdd.2017.130. (Epub ahead of print)
Smith AJ, Lewis FC, Aquila I, Waring CD, Agosti V, et al. Isolation and characterisation of resident endogenous c-kit-positive cardiac stem cells (eCSCs) from the adult mouse and rat heart. Nat. Prot. 9(7): 1662-1681 (2014).
Vicinanza C, Aquila I, Scalise M, Cristiano F, Marino F, Cianflore E, Mancuso T, Marotta P, Sacco W, Lewis FC, Couch L, Shone V, Gritti G, Torella A, Smith AJ, Terracciano CMN, Britti D, Veltri P, Indolfi C, Nadal-Ginard B, Ellison-Hughes GM, Torella D (2017) Adult cardiac stem cells are multipotent and robustly myogenic: c-kit expression is necessary but not sufficient for their identification. Cell Death and Differentiation doi: 10.1038/cdd.2017.130. (Epub ahead of print)
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Career overview
Dr Andrew Smith completed a medical degree (MBChB) at the University of Aberdeen in 2001 and subsequently worked clinically for several years. He pursued a research PhD in Neuroscience and Biomedical Systems at the University of Glasgow, which he completed in 2008. Following his doctoral studies, Dr Smith worked as a post-doctoral researcher at Liverpool John Moores University from 2009 to 2013, and then at King''s College London from 2013 to 2015. He is currently a Lecturer in Cardiovascular Science at the University of Leeds, where he also leads the MBiol Programme in the School of Biomedical Sciences and serves as the Admissions Tutor for the school.
Research interests
Dr. Smith''s research focuses on cardiac regeneration, cardiovascular stem and progenitor cells, and cardiotoxicity. A primary interest is in the role of endogenous cardiac progenitor cells (CPCs) in myocardial tissue maintenance and repair. His group investigates how these cells contribute to normal myocardial function and respond to injury, demonstrating their potential to differentiate into various cell types and repair myocardial tissue. Dr. Smith''s previous work has highlighted the critical role of CPCs in myocardial tissue maintenance following diffuse cardiac injury and the potential for growth factors to enhance their activity and improve recovery after myocardial infarction. Additionally, Dr. Smith is currently examining the effects of receptor tyrosine kinase inhibitors (RTKIs), which are known cardiotoxins, on CPCs. His research explores how these anti-cancer drugs impact CPC phenotype, self-renewal, differentiation, and the pro-survival secretome, as well as their overall effects on heart function. This work aims to identify new treatment avenues for RTKI-induced cardiotoxicity and to leverage CPCs'' regenerative potential for heart failure treatment. Another significant area of Dr. Smith''s research involves understanding cell death mechanisms in CPCs induced by RTKIs, focusing on the pathways involved and associated changes in intracellular calcium and reactive oxygen species levels. This study employs various techniques, including cell culture and confocal analysis, to elucidate the toxic effects of RTKIs on cardiac cells. Dr. Smith''s group is also developing a novel method for non-destructive cell protein ''biopsy'' using amphipathic polymers, which allows for the extraction of proteins from cells without causing cell death. This method has been successfully applied to human cardiovascular cells and aims to identify biomarkers for early vascular complications of diabetes mellitus. Overall, Dr. Smith''s research encompasses a broad range of topics within cardiovascular science, with a strong emphasis on the biology of cardiac progenitor cells and their potential therapeutic applications.
Cardiac Regeneration
Cardiovascular Stem Cells
Progenitor Cells
Cardiotoxicity
Cell Culture
Myocardial Tissue Maintenance
Endogenous Cardiac Progenitor Cells
High-Intensity Exercise
Receptor Tyrosine Kinase Inhibitors
Cell Death Mechanisms
Non-Destructive Cell Biopsy
Amphipathic Polymers
Protein Expression
Biomarkers
Heart Failure
Regenerative Potential
Cardiovascular Science
Admissions Tutor
Medical Degree
PhD in Neuroscience
Post-Doctoral Research
Research Interests
Cardiovascular Tissue
Myocardial Function
Tissue Repair
Growth Factors
Functional Recovery
Cell Signalling Mechanisms
Clinical Research
Collaborative Studies.
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