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Rosetrees Trust funded project

last modified Jul 21, 2020 10:49 AM
Dr Cathy Wilson and Dr Paul Miller are awarded Rosetrees-Cambridge Innovation & Translation 2020 Awards to pioneer approaches in cardiac regeneration and CNS antibody delivery, respectively...

Dr. Paul Miller:

Understanding and engineering central nervous system shuttles to target biologics against GABA-A receptors

Central nervous system (CNS) disorders include anxiety, depression, insomnia, Alzheimer’s, Parkinson’s, schizophrenia, chronic pain, epilepsy and autism. They represent a huge challenge to society and bear enormous economic cost. Drug treatments are almost exclusively small molecules, usually with limited efficacy and many side effects. Substantial improvements could be realised by developing biologics (antibodies) to behave like drugs, as these possess supreme specificity for their molecular target. However, a major challenge exists because antibodies are not able to cross the blood brain barrier (BBB) to penetrate the CNS. One solution is to use ‘Trojan horse’ antibodies, which bind a target on the BBB and ferry a physically attached cargo, for example, a therapeutic antibody, across it into the CNS.

In this Rosetrees Trust funded project we will apply structural biology techniques to look in high resolution detail at how such Trojan horse antibodies interact with their molecular targets. This will provide detailed information on the interaction process. Guided by this we will design novel Trojan horse antibodies with improved properties for superior delivery of therapeutic antibodies to treat neurological disorders.

Dr. Cathy Wilson:

Developing a single nuclei transcriptional toolkit to examine cardiac regeneration in adult mice

The cells in adult heart muscle, the cardiomyocytes, do not have the capacity to regenerate by proliferating after injury. Significant injury to these tissues can have life-threatening or disabling consequences, and major research efforts are therefore aimed at regenerating these tissues. We have been able to demonstrate that if we force the expression of two genes, Myc and Cyclin T1, in cardiomyocytes in mouse hearts via genetic manipulation, we can elicit a substantial proliferative response.

Accurate identification of cardiomyocytes is crucial for the examination of regenerative processes in the myocardium. We will establish a method for single nuclei cardiomyocyte transcriptional analysis. The method will enable the determination of transcriptional changes and heterogeneity that occur during cardiomyocyte proliferation induced by Myc and Cyclin T1. A successful outcome would be a significant step forward in regenerative cardiology and provide new insight into the molecular and cellular mechanisms required for regeneration.

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