Objective
The loss of structural integrity in the interphase nucleus leads to tissue-specific pathologies in a set of human diseases collectively called laminopathies. These are late-onset, tissue-specific degenerative diseases, such as Emery Dreifuss Muscular Dystrophy (EDMD). While rare, these conditions provide insight into more common degenerative disorders linked to aging. A Caennorhabditis elegans mutant that recreates the EDMD phenotypes arises from introduction of a specific gain-of-function mutation into lamin (LMN-1 Y59C), which in turn affects the subnuclear distribution of muscle-specific promoters. This proposal plans to identify novel factors that establish and/or maintain the 3D organization of the genome in differentiated nuclei and to determine how this contributes to the differentiated muscle cell fate. I propose that compromised or altered sequestration of chromatin at the nuclear envelope alters cell-type specific promoter induction and in turn compromises the integrity of the tissue in question.
The specific aims of the project are 1) To identify factors that establish and/or maintain 3D genome organization in muscle nuclei. 2) To determine if the integrity of the perinuclear chromatin binding machinery helps maintain differentiated cell states. 3) To test inhibitors of epigenetic regulators for compounds that overcome the EDMD-like LMN-1 Y59C mutation. I will take two complementary approaches to determine how muscle specific chromatin organization maintains tissue integrity. I will use in vivo biochemical tagging in the LMN-1 Y59C mutant to identify perinuclear components that mediate sequestration of muscle-specific gene promoters. In parallel, a drug screen will find compounds that reverse the nuclear disorganization linked to the EDMD-like phenotype. The pathways identified will explain how lamin-induced mis-organization of the genome influences muscle integrity, a topic relevant for muscular dystrophies, sarcopenia, and other degenerative disease.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences basic medicine neurology muscular dystrophies
- natural sciences biological sciences genetics mutation
- medical and health sciences basic medicine pathology
- medical and health sciences basic medicine physiology
- natural sciences biological sciences genetics genomes
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
MSCA-IF-EF-ST - Standard EF
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2016
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
4056 BASEL
Switzerland
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.