Supervisor:   Dr David Connolly

Department:  Clinical Science and Services

Canine cardiomyopathies cause significant morbidity and mortality Myocardial inflammation is the key to disease initiation and progression. Cardiosphere derived cells (CDCs) are used therapeutically but efficacy to date has been suboptimal potentially because CDCs cause only transient benefit due to their rapid elimination from the myocardium. Stem cell therapy acts via paracrine mechanisms that can be exploited by isolating microvesicles (MVs) which can be repeatedly administered intravenously enabling prolonged therapeutic benefit. In a pivotal study systemic delivery of MVs from human CDCs in a mouse DCM model improved heart function and angiogenesis and decreased apoptosis and fibrosis. Therapeutic potential can be improved by strategies to enhance the anti-inflammatory, anti-apoptotic and proangiogenic activity of MVs derived from CDCs by hypoxic preconditioning (HP) driving upregulation of hypoxia inducible factor (HIF).

Hypothesis: MVs derived from HP CDCs will have enhanced anti-apoptotic, reparative and pro-angiogenic activity measured by established in vitro functional assays

Aims: Compare the efficacy of MVs from HP CSCs (5% O2) with MVs from CSC cultured at 21%O2 to mitigate injury responses using established in vitro models. Output measures: Scratch assay for wound healing, apoptosis, and pro-angiogenesis assays.

  

References

  1. Gallet R, Dawkins J, Valle J, Simsolo E, de Couto G, Middleton R, Tseliou E, Luthringer D, Kreke M, Smith RR, Marban L, Ghaleh B, Marban E. Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction. Eur Heart J. 2017 Jan 14;38(3):201-211.
  2. Vandergriff AC, de Andrade JB, Tang J, Hensley MT, Piedrahita JA, Caranasos TG, et al. Intravenous cardiac stem cell-derived exosomes ameliorate cardiac dysfunction in doxorubicin induced dilated cardiomyopathy. Stem Cells Int. 2015;2015:960926.
  3. Tanaka Y, Hosoyama T, Mikamo A, Kurazumi H, Nishimoto A, Ueno K, Shirasawa B, Hamano K. Hypoxic preconditioning of human cardiosphere-derived cell sheets enhances cellular functions via activation of the PI3K/Akt/mTOR/HIF-1α pathway. Am J Transl Res. 2017 Feb 15;9(2):664-673.
  4. RajendranNair DS, Karunakaran J, Nair RR. Sub-physiological oxygen levels optimal for growth and survival of human atrial cardiac stem cells. Mol Cell Biochem. 2017 Aug;432(1-2):109-122

  

Requirements

Applicants should hold or expect to achieve a First or 2:1 degree in biological sciences preferably with an immunological bias.

They should be highly motivated and proactive.

  

This is a full-time 12 Month project commencing in October 2019.

Money for all consumables has been secured for this project

We welcome informal enquiries - these should be directed to dconnolly@rvc.ac.uk

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