Michael Hagemann-Jensen

Alternative splicing is a complex process influenced by a multitude of factors enabling cells to produce different protein variants from the same gene, thereby increasing cellular phenotypic diversity. While it is a highly used mechanism for immune cells to fine-tune and adapt their responses to various challenges, aberrant splice patterns are frequently found in dysfunctional T-cells, potentially compounding their defects. However, there is a profound lack of understanding about how splicing decisions are regulated during different stages of T-cell development and activation, the heterogeneity of used splice events, underlying signaling networks, and ultimately their functional consequences in T-cells. In this proposal we aim to tackle these questions and advance our understanding of splicing regulation in T-cells. We will gain a comprehensive, genome-wide understanding of alternative splicing dynamics and regulation through the development of novel multi-modal single-cell technologies and vitro differentiation and stimulation assays of human T-cells. We will uncover splicing variation and contribution to T-cell response as well as elucidate functional consequences through CRISPR interference screens. Uncovering the molecular mechanisms of splicing has immense clinical implications. We anticipate that it will be crucial to remedy immune mediated diseases and could lead to more accurate engineering of T-cells, as well as strategies to revert cells out of dysfunctional states.

Immature cardiorespiratory control in infants may result in apneas, sudden unexpected postnatal collapse (SUPC), secondary hypoxic brain damage and SIDS. We have shown that prostaglandins are central pathogenic factors in respiratory disorders and the hypoxic response. This has led us to focus on the role of inflammation and brainstem modulation in both clinical and mechanistic studies. These are used to define mechanisms for factors disturbing the physiological and neural pathways that control breathing. main goals are:1) Develop better clinical guidelines and best practices for respiratory failures in newborns e.g. Sudden Unexpected Postnatal Collapse (SUPC).2) To clinically characterize how dysregulation of respiratory control induces life-threatening apneas and if subtle alterations in cardiorespiratory parameters may act as early warning scores for infection, inflammation and a need for increased intervention. Patients recruited at the Pediatric wards and with the help of KTH expertise we use Deep Machine Learning based analysis to develop rapid semiautomatic Novel Early Warning Systems3) To define the pathophysiological mechanism of apneas and involvement of inflammation in the development and activity of brainstem respiration-related neural circuits. In vivo and novel in vitro experimental mouse models and single cell transcriptomics techniques are used.The overall aim is to develop diagnostics and therapeutic approaches against life threatening apneas and collapse.