ERC FUNDED PROJECTS

Dysregulation of capillary permeability is a severe problem in critically ill patients, but the mechanisms involved are poorly understood. Further, there are no targeted therapies to stabilize leaky vessels in various common, potentially fatal diseases, such as systemic inflammation and sepsis, which affect millions of people annually. Although a multitude of signals that stimulate opening of endothelial cell-cell junctions leading to permeability have been characterized using cellular and in vivo models, approaches to reverse the harmful process of capillary leakage in disease conditions are yet to be identified. I propose to explore a novel autocrine endothelial permeability regulatory system as a potentially universal mechanism that antagonizes vascular stabilizing ques and sustains vascular leakage in inflammation. My group has identified inflammation-induced mechanisms that switch vascular stabilizing factors into molecules that destabilize vascular barriers, and identified tools to prevent the barrier disruption. Building on these discoveries, my group will use mouse genetics, structural biology and innovative, systematic antibody development coupled with gene editing and gene silencing technology, in order to elucidate mechanisms of vascular barrier breakdown and repair in systemic inflammation. The expected outcomes include insights into endothelial cell signaling and permeability regulation, and preclinical proof-of-concept antibodies to control endothelial activation and vascular leakage in systemic inflammation and sepsis models. Ultimately, the new knowledge and preclinical tools developed in this project may facilitate future development of targeted approaches against vascular leakage.

1 999 770 €

Start date: 2018-05-01, End date: 2023-04-30

Resilience and recovery ability are key determinants of species persistence and viability in a changing world. Populations exposed to rapid environmental changes and human-induced alterations are often affected by both ecological and evolutionary processes and their interactions, that is, eco-evolutionary dynamics. The integrated perspective offered by eco-evolutionary dynamics is vital for understanding drivers of resilience and recovery of natural populations undergoing rapid changes and exposed to multiple stressors. However, the feedback mechanisms, and the ways in which evolution and phenotypic changes scale up to interacting species, communities, and ecosystems, remains poorly understood. The objective of my proposal is to bridge and close this gap by merging the fields of ecology and evolution into two interfaces of complex biological dynamics. I will do this in the context of conservation and sustainable harvesting of aquatic ecosystems. I will develop a novel mechanistic theory of eco-evolutionary ecosystem dynamics, by coupling the theory of allometric trophic networks with the theory of life-history evolution. I will analyse the eco-evolutionary dynamics of aquatic ecosystems to identify mechanisms responsible for species and ecosystem resilience and recovery ability. This will be done through systematic simulation studies and detailed analyses of three aquatic ecosystems. The project delves into the mechanisms through which anthropogenic and environmental drivers alter the eco-evolutionary dynamics of aquatic ecosystems. Mechanistic understanding of these dynamics, and their consequences to species and ecosystems, has great potential to resolve fundamental yet puzzling patterns observed in natural populations and to identify species and ecosystem properties regulating resilience and recovery ability. This will drastically change our ability to assess the risks related to current and future anthropogenic and environmental influences on aquatic ecosystems.

1 999 391 €

Start date: 2018-06-01, End date: 2023-05-31

The ageing population structure of most European countries has major health, economic and social consequences that lead to a need to better understand both the evolutionary limitations of deferring ageing, as well as the mechanisms involved in growing old. Ageing involves reduced fertility, mobility and ability to combat disease, but some individuals cope with growing old better than others. Improving the quality of life at old age and predicting future changes in longevity patterns of societies might depend on our ability to develop indicators of how old we really are and how many healthy years we have ahead, and how those indicators depend on our health history across several decades. Yet, most model species used in biology are short-lived and provide a poor comparison to long-lived mammals such as humans. Further, they do not often inform on the mechanisms of ageing alongside its fitness consequences in natural populations of long-lived mammals. This project integrates different ageing mechanisms with unique data on lifelong disease and reproductive history in the most long-lived non-human mammal studied so far, the Asian elephant. I will examine how different mechanisms of ageing (telomere dynamics, oxidative stress and telomerase activity) interact with lifelong disease and reproductive history, and current endocrinological measures of stress and reproductive status. This will help us to better understand both the mechanisms of ageing and their consequences on senescence rates. To do so, I will combine the most comprehensive demographic data (N~10.000) on Asian elephants in the world with bi-monthly health assessments and disease records across life (N~2500) and with longitudinal markers of ageing and hormonal correlates of stress and reproductive potential (N~240). Understanding changes in health across life and its links to ageing rates, stress levels and life-history in a species as long-lived as humans will be relevant to a large range of end-users.

1 949 316 €

Start date: 2016-01-01, End date: 2021-12-31

Molecular pathogenesis of most immune-mediated disorders, such as of autoimmune diseases, is poorly understood. These common maladies carry a heavy burden both on patients and on society. Current therapy is non-targeted and results in significant short- and long-term adverse effects. Large granular lymphocyte (LGL) leukemia is characterized by expansion of cytotoxic T- or NK-cells and represents an intriguing clinical continuum between a neoplastic and an autoimmune disorder. Patients suffer from autoimmune cytopenias and rheumatoid arthritis (RA), which are thought to be mediated by LGL cells targeting host tissues. My group recently discovered that 40-50% of LGL leukemia patients carry in their lymphoid cells acquired, activating mutations in the STAT3 gene – a key regulator of immune and oncogenic processes (Koskela et al, N Engl J Med, 2012). This breakthrough discovery gives insight to the pathogenesis of autoimmune disorders at large. I present here a hypothesis that a strong antigen-induced proliferation is a mutational driver, which causes somatic mutations in lymphoid cells. When mutations hit key activating pathways, autoreactive cells acquire functional advantage and expand. The target antigen of the expanded clone determines the clinical characteristics of the autoimmune disease induced. To prove this hypothesis, we will separate small lymphocyte clones from patients with autoimmune diseases and use sensitive next-generation sequencing methods to characterize the spectrum of somatic mutations in lymphoid cells. Further, we will study the function of mutated lymphocytes and examine the mechanisms of autocytotoxicity and end-organ/tissue damage. Finally, we aim to understand factors, which induce somatic mutations in lymphoid cells, such as the role of viral infections. The results will transform our understanding of molecular pathogenesis of autoimmune diseases and lead to accurate diagnostics and discovery of novel drug targets.

2 047 337 €

Start date: 2015-09-01, End date: 2021-02-28