SHARP Research Projects

Hematopoietic stem cells (HSC) are responsible for producing blood and immune cells throughout the lifespan of an organism. With age, HSCs show reduced regenerative potential, aberrant differentiation, transcriptional alterations and dysregulation of signalling pathways. In this project, we will characterise transcriptional changes and proteome remodelling in ageing HSCs of mice deficient for GSK-3 (Glycogen Synthase Kinase-3), a master regulator of the mammalian target of rapamycin (mTOR) pathway. We will also determine the effects of mTOR inhibitors as a therapeutic approach for blood rejuvenation.

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In the process of ageing, DNA undergoes certain modifications, the most interesting of which is cytosine methylation. These changes allow researchers to determine epigenetic age, which is reflected in “epigenetic clocks" - a defined pattern of methylation states at CpG islands. Epigenetic age not only accurately indicates chronological age, but also provides information about a person‘s health status. In this project, we will investigate the utility of epigenetic clocks (e.g. the well-known Horvath clock) in heart failure (HF) syndrome. The epigenetic age of patients with HF will be evaluated using novel machine learning techniques to predict disease status and outcome. Ideally, this may result in computational tools for guidance of treatment in the future.

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Age-related defects in the immune system increase the chance of infections, cancer, and autoimmunity in the elderly. These defects largely centre on changes in T cell responsiveness. In this project, we will investigate how BRG1- or BRM-associated factor (BAF) complexes regulate FOXP3 expression in T_REG cells and the implications for immune ageing. We will use conditional knockout mouse models combined with proteomics, genomics, molecular biology, CRISPR/Cas9, flow cytometry and imaging, as well as various functional assays.

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Little is known about how the nervous system of the gut (called the enteric nervous system or ENS) changes with age. Initial results indicate that functional decline in the ENS with age is strongly correlated to age-related diseases of the central nervous system. The aim of this project is to decipher how the ENS changes during healthy and diseased (Alzheimer’s) ageing and how these changes affect the gut, its function, and its interaction with the ageing brain. This may open up new diagnostic approaches and treatment options for patients suffering from neurodegenerative diseases.

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Chromosome copy number alterations often occur during ageing, the most frequent being losses of the sex chromosomes. The aim of this project is to study the prevalence, physiological relevance and dynamic cellular response mechanisms associated with chromosome loss during ageing. We will develop a cellular tool allowing the inducible loss of a specific chromosome and then dissect cellular responses upon chromosome loss in stem cells and terminally differentiated tissues. Our studies will provide important insights into the relevance of sex-specific gene expression and the sex chromosome complement for ageing and longevity.

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Long non-coding transcripts from subtelomeric and telomeric sequences (called telomere repeat-containing RNA, or “TERRA”) orchestrate telomere maintenance, but can also lead to telomere loss if not properly regulated. Evidence suggests that telomere length and telomere signalling has a significant role in the pathogenesis of heart failure (HF). TERRA-containing exosomes from blood plasma have also been shown to induce inflammation, which is a key determinant of lesion size and recovery after myocardial injuries. In this project, we will investigate the contribution of TERRA in telomere maintenance/loss in HF, the influence of extracellular/secreted TERRA on myocardial inflammation, and whether TERRA contributes to the development of HF after myocardial infarction.

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Chronic inflammation is a source of many age-related problems, including cancer, obesity, cardiovascular and neurological diseases. The tumour suppressor gene CYLD is a key component of the ubiquitin system, which regulates the pro-inflammatory NF-κB signalling pathway. We previously identified a short splice variant of CYLD (sCYLD) that is overexpressed in some lymphomas. This project will elucidate the relevance of sCYLD to ageing. We will analyse mice with CYLD deficiency, as well as mice exclusively expressing sCYLD, for age-related problems. In addition, we will analyse the signalling complexes in the NF-κB pathway to understand how CYLD and sCYLD regulate NF-κB signalling.

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Ageing is associated with an accumulation of damaged proteins and toxic protein aggregates in the cell. These misfolded, damaged or aggregated proteins are removed by the ubiquitin-proteasome system and the autophagy-lysosome pathway. This project will investigate how ubiquitylation and protein degradation is affected during cellular ageing, especially after induction of autophagy by starvation or genotoxic stress. We will use cell models to systematically characterise changes in the proteome, ubiquitylome and autophagic activity to better understand the relevance of changes in protein quality control to ageing.

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β₂ integrins are essential for proper cell function in leukocytes. We previously showed that mice with knockouts of the β₂ integrin subunit CD18 lack T cells in their skin and develop an age-dependent psoriasis-like phenotype. This project aims to determine the role of skin-resident T cells in tissue homeostasis, and the contribution of β₂ integrins to T cell immunosenescence. We will perform in-depth transcriptome and flow cytometry analyses of keratinocytes/fibroblasts and skin-resident T cells in young versus old mice. This study will improve our understanding of the mechanisms behind age-related skin diseases.

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DNA repair is one of the most important factors preventing premature ageing. Moreover, defects in many DNA repair pathways influence neural function. Compound heterozygous or homozygous mutations in BRCA2, an important DNA repair factor, cause Fanconi anemia Type D, a congenital disease accompanied by microcephaly, developmental delay and intellectual disability. This project aims to elucidate the mechanisms that link BRCA2 to cognitive function and decline. We will characterise DNA replication and repair in induced pluripotent stem (iPS) cells from patients and cell lines engineered by CRISPR/Cas, and study the consequences of BRCA2 depletion for brain development, behaviour and cognitive function in mice with age.

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Glioblastoma management is exceedingly complex in elderly patients due to frequent comorbidities and a higher risk of toxic effects from chemo- and radiation therapy in ageing brains. The aim of this study is to develop a tool to predict patient outcomes by measuring biological age and ‘frailty’ so that therapies can be tailored to individuals. We will correlate patient treatment responses with their frailty index and with molecular characteristics from samples taken prior to and over the course of treatment. This will allow us to better predict treatment outcomes for elderly patients with glioblastoma and aid in future treatment decisions.

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In sporadic neurodegenerative diseases such as Alzheimer’s, some brain regions (e.g. the prefrontal cortex, PFC) are more vulnerable, while others (e.g. the cerebellum) retain functional integrity even at late stages of disease. We will combine transcriptomic and biochemical approaches to identify altered molecular patterns underlying cerebral ageing and neurodegeneration in mouse models of accelerated senescence, which can be used to guide future studies in human patients.

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Age-related changes in the immune system and premature immunosenescence increase vulnerability to multiple diseases, thereby reducing both longevity and quality of life. The aim of this project is to develop brain-specific senescence signatures of immune cells in health, inflammation and neurodegeneration. We will analyse markers of immunosenescence in the cerebrospinal fluid of young, middle-aged and old individuals to develop brain-specific senescence signatures, and then compare these to the immunosenescence signatures of patients with neurodegenerative disease and multiple sclerosis, an immune-mediated neurodegenerative disorder of the brain. This study will improve our understanding of the age-associated changes that occur in immune cells and how they contribute to neuroinflammation and neurodegeneration.

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