ERC FUNDED PROJECTS

Previous research has investigated the relationship between unemployment and health from a perspective of an isolated individual. HEALFAM takes a novel approach and examines how transition to unemployment triggers diffusion of ill mental and physical health within families. It investigates how becoming unemployed affects health outcomes of partners, children and elderly parents of the unemployed and whether the magnitudes of these influences differ across families and societies. Thus, instead of viewing the unemployed as functioning in isolation, HEALFAM assesses the consequences of unemployment for family members taking a multi-actor perspective and international comparative approach. Guided by the life course theoretical framework, which views health and well-being as a process rather than a state and calls for considering interrelatedness of individuals, HEALFAM employs longitudinal data that provide information about multiple members of families. In order to analyse these datasets, HEALFAM uses longitudinal dyadic data analysis techniques as well as multilevel models for longitudinal data. HEALFAM aims to open a new frontline of research on health and wellbeing from a life course perspective. It benefits from my knowledge on three interrelated social phenomena: (1) the role of labour market career and experiences of unemployment (2) family structure and intra-family resources (3) social antecedents of health and wellbeing among family members. It draws on high quality register and panel survey data as well as the expertise at the interdisciplinary research centres that I am connected to at Umeå University. Through international collaborations, it brings together experts in multiple disciplines carrying out research taking a life course perspective.

1 477 556 €

Start date: 2019-03-01, End date: 2024-02-29

The length of telomeric DNA is a critical determinant factor for aging and cancer development. In germ cells, the activation of a telomerase-dependent telomere-lengthening pathway is thought to be important in order to maintain telomeric DNA across generations, but the molecular mechanisms involved in this pathway, i.e: how and when telomerase is activated in germ cells, are largely unknown. A DNA-binding protein complex called shelterin constitutively binds telomeric DNA. However, my recent studies have suggested that a multi-subunit DNA-binding complex, TERB1-TERB2-MAJIN, takes over telomeric DNA from shelterin in mammalian germ cells in order to facilitate homologous recombination. These findings represent a hitherto unknown molecular mechanism at work on the telomeres in germ cells. In this project, I hypothesize that the drastic reformation of telomere-binding complexes in germ cells contributes also to the telomere-lengthening pathway. The aim of this project is to test this hypothesis in order to reveal the mechanism underlying the transgenerational inheritance of telomeric DNA throughout meiosis. This work is divided into three work packages. WP1: to determine the molecular rearrangements that take place at telomeres during meiosis. WP2: to determine how and when telomeres are lengthened during germ cell production. WP3: to determine how meiotic recombination is achieved. The proposed project will reveal molecular mechanisms underlying the transgenerational inheritance of genetic information after meiosis, and this will increase our understanding of the etiology of numerous human diseases caused by meiotic errors, such as congenital birth defects and aneuploidy. Further, because the misregulation of telomerase is a leading cause of cancer development, the identification of telomerase-activating mechanisms in germ cells will have multidiscipline impacts in both cancer and reproductive biology fields and will be useful for developing novel cancer therapies.

1 500 000 €

Start date: 2019-01-01, End date: 2023-12-31

It is now becoming apparent that genes are regulated not only by transcription, but also by thousands of post-transcriptional regulators that can stabilize or degrade mRNAs. Some of the most important regulators are miRNAs, short RNA molecules that are deeply conserved in sequence and are involved in numerous biological processes, including human disease. Surprisingly, transcriptomic and proteomic studies show that most miRNAs only have subtle silencing effects on their targets, suggesting additional important, but yet undiscovered functions. Thus the question is raised: if the main function of miRNAs is not to silence targets, what is it? I will test two novel hypotheses about miRNA function. The first hypothesis proposes that miRNAs can buffer gene expression noise. The second hypothesis is inspired by my preliminary results and proposes that miRNAs can synchronize expression of genes. If I validate either hypothesis, it would mean that miRNA functions can be investigated in entirely new ways, yielding important new biological insights relevant to both basic research and human health. However, these hypotheses can only be tested in individual cells, and the necessary single-cell technologies and computational tools are only maturing now. I will apply my expertise in miRNA biology and in combined wet-lab and computational methods to design, develop and apply miRCell-seq to test these two hypotheses in cell cultures and in animals. This new method will for the first time measure miRNAs, their targets, and the interactions between them in single cells and transcriptome-wide. We will use mutant cells devoid of miRNAs and time course experiments to generate sufficient data to develop detailed models of the miRNA impact on their targets. We will then validate our findings with single cell proteomics. This project thus has the potential to reveal novel functions of miRNAs and substantially improve our general understanding of gene regulation.

1 497 650 €

Start date: 2018-03-01, End date: 2023-02-28

Oxygen (O2) levels can vary enormously in the environment, which induces dramatic behavioral and physiological changes to resident animals. Adaptations to O2 variations can be either acute or sustained. How animals detect and respond to the changes of O2 availability remains elusive at the molecular level. In particular, what is the precise mechanism of acute O2 sensing, what are the primary sensor for acute hypoxia, and why do neurons of various species exhibit completely different sensitivity to hypoxic challenges? The research proposed here aims at addressing these intriguing but challenging questions in the model system nematode C. elegans, which offers unique advantages to systematically dissect O2 sensing at both genetic and neural circuit levels. C. elegans responds dramatically to acute O2 variations by altering its locomotory speed. We will make use of this robust behavioral response to O2 stimulation for high-throughput genetic screens, aiming to identify a collection of molecules critical for acute O2 sensing. These molecules will be subsequently characterized in the context of a well-described nervous system of C. elegans. Our findings will offer the opportunity to shed light on conserved principles of acute O2 sensing that are operating in the O2 sensing systems in humans such as carotid body. In addition to its robust responses to O2 variation, C. elegans exhibits remarkable tolerance to a complete lack of O2, anoxic exposure. My team will thoroughly investigate anoxia tolerance of C. elegans by performing a screen for anoxia-sensitive mutants that has previously been challenging. The discoveries will allow us to delineate the molecular underpinning of anoxia tolerance in C. elegans, and to inspire other researchers to develop better strategies to cope with hypoxic challenges caused by certain diseases such as stroke and ischemia, which are the most causes of human deaths in developed countries.

1 485 000 €

Start date: 2019-01-01, End date: 2023-12-31