ERC FUNDED PROJECTS

Faithful repair of double stranded DNA breaks (DSBs) is essential, as they are at the origin of genome instability, chromosomal translocations and cancer. Cells repair DSBs through different pathways, which can be faithful or mutagenic, and the balance between them at a given locus must be tightly regulated to preserve genome integrity. Although, much is known about DSB repair factors, how the choice between pathways is controlled within the nuclear environment is not understood. We have shown that nuclear architecture and non-random genome organization determine the frequency of chromosomal translocations and that pathway choice is dictated by the spatial organization of DNA in the nucleus. Nevertheless, what determines which pathway is activated in response to DSBs at specific genomic locations is not understood. Furthermore, the impact of 3D-genome folding on the kinetics and efficiency of DSB repair is completely unknown. Here we aim to understand how nuclear compartmentalization, chromatin structure and genome organization impact on the efficiency of detection, signaling and repair of DSBs. We will unravel what determines the DNA repair specificity within distinct nuclear compartments using protein tethering, promiscuous biotinylation and quantitative proteomics. We will determine how DNA repair is orchestrated at different heterochromatin structures using a CRISPR/Cas9-based system that allows, for the first time robust induction of DSBs at specific heterochromatin compartments. Finally, we will investigate the role of 3D-genome folding in the kinetics of DNA repair and pathway choice using single nucleotide resolution DSB-mapping coupled to 3D-topological maps. This proposal has significant implications for understanding the mechanisms controlling DNA repair within the nuclear environment and will reveal the regions of the genome that are susceptible to genomic instability and help us understand why certain mutations and translocations are recurrent in cancer

1 999 750 €

Start date: 2017-03-01, End date: 2022-02-28

Alzheimer's disease, the most common cause of dementia in older people, is a devastating condition that is becoming a public health crisis as our population ages. Despite great progress recently in Alzheimer’s disease research, we have no disease modifying drugs and a decade with a 99.6% failure rate of clinical trials attempting to treat the disease. This project aims to develop relevant therapeutic targets to restore brain function in Alzheimer’s disease by integrating human and model studies of synapses. It is widely accepted in the field that alterations in amyloid beta initiate the disease process. However the cascade leading from changes in amyloid to widespread tau pathology and neurodegeneration remain unclear. Synapse loss is the strongest pathological correlate of dementia in Alzheimer’s, and mounting evidence suggests that synapse degeneration plays a key role in causing cognitive decline. Here I propose to test the hypothesis that the amyloid cascade begins at the synapse leading to tau pathology, synapse dysfunction and loss, and ultimately neural circuit collapse causing cognitive impairment. The team will use cutting-edge multiphoton and array tomography imaging techniques to test mechanisms downstream of amyloid beta at synapses, and determine whether intervening in the cascade allows recovery of synapse structure and function. Importantly, I will combine studies in robust models of familial Alzheimer’s disease with studies in postmortem human brain to confirm relevance of our mechanistic studies to human disease. Finally, human stem cell derived neurons will be used to test mechanisms and potential therapeutics in neurons expressing the human proteome. Together, these experiments are ground-breaking since they have the potential to further our understanding of how synapses are lost in Alzheimer’s disease and to identify targets for effective therapeutic intervention, which is a critical unmet need in today’s health care system.

2 000 000 €

Start date: 2016-11-01, End date: 2021-10-31

"What kinds of self does it take to make a revolution? And how does revolutionary politics, understood as a project of personal as much as political transformation, articulate with other processes of self-making, such as religious practices? Comparative Anthropologies of Revolutionary Politics (CARP) seeks fundamentally to recast our understanding of revolutions, using their relationship to religious practices in diverse social and cultural settings as a lens through which to reveal revolutions’ varied capacities for self-making. Developing a comparative matrix of revolutionary settings in the Middle East, Latin America and elsewhere, CARP’s core objective is to investigate the differing permutations and dynamics of revolutionary ‘anthropologies’ in the original theological sense of the term, i.e. charting revolutionary politics in relation to varying conceptions of what it is to be human, and of how the horizons of people’s lives are to be understood in relation to divine orders of different kinds, in order to reveal how revolutions come to define what persons may be, deliberately setting the social, political, cultural and ultimately ontological coordinates within which people are made who they are. Bringing close ethnographic investigation to bear on conceptions of revolution, statecraft, and subjectivity in political theory, CARP will produce comprehensive political ethnographies of nine major case-studies, comparing systematically the relationship between revolution and religion in a selection of countries in the Middle East and Latin America. Four smaller-scale case-studies from Europe and Asia will add complementary dimensions to this comparative matrix. Providing much-needed empirical materials and analytical insight into the dynamic comingling of political and religious forms in the making of revolutionary selves, CARP’s ultimate ambition is to launch the comparative study of revolutionary politics as a major new departure for anthropological research."

1 854 472 €

Start date: 2014-06-01, End date: 2019-05-31

How has foreign occupation shaped culture? What has been the lasting cultural legacy of foreign occupation in those societies where it represented the usual state of affairs for much of the modern era? These are key questions which, in light of ongoing cases of occupation around the world, remain crucial in the 21st century. Cultures of Occupation in Twentieth-century Asia (COTCA) will answer these questions by analysing how occupation―be it under colonial, wartime or Cold War powers―gave rise to unique visual, auditory and spatial regimes in East and Southeast Asia. The core objective of this important project is to produce a paradigm shift in the study of occupation, and to challenge the 'collaboration'/'resistance' dichotomy which has defined the field thus far. It will adopt a transnational, intertextual and comparative approach to the study of cultural expression produced under occupation from the 1930s to the 1970s. It will also break new methodological ground by drawing on and contributing to recent developments in visual, auditory and spatial history as a means of highlighting intersections and cultural convergences across different types of occupation. By doing so, COTCA will, for the first time, determine what occupation looked, sounded and felt like in twentieth-century Asia. The COTCA team will consist of the PI, 2 postdoctoral researchers and 3 PhD students, and will run along 3 streams: (i) Representations of occupation; (ii) sounds of occupation; and (iii) spaces of occupation. Case studies based on hitherto rarely examined examples will be undertaken in each stream. These include: A visual history of Japanese-occupied China; soundscapes of the US naval bases in the Philippines; and, spaces of occupation in late-colonial Malaya. COTCA will also build a Digital Archive which will enable researchers to trace the development of narratives, tropes and motifs common to 'occupation' cultural expression in Asia across national and temporal borders.

1 885 268 €

Start date: 2016-07-01, End date: 2022-06-30