PRIN 2017 - 2017FNZRN3_005 - LS2 - Dott.ssa LAVIA- Titolo: "Microtubule and centrosome dynamics, from Omics to neurodevelopmental disorders of Central Nervous System" (DSB.AD006.256)

Thematic area

Biomedical sciences

Project area

Structure responsible for the research project

Institute of molecular biology and pathology (IBPM)

Project manager

PATRIZIA LAVIA
Phone number: 0649912756
Email: patrizia.lavia@uniroma1.it

Abstract

Genes acting in assembly/functions of the mitotic spindle microtubules (MTs), centrosomes, kinetochores (KTs) and chromatin remodelling are implicated in neurodevelopmental disorders (NDDs). This project will employ several model systems to develop functional assays of genes identified as causative of NDDs. New protein partners will be identified by proteomics analyses using bioinformatics, and hence pathways, implicated in NDDs. Libraries of compounds will be screened using yeast to identify those that can overcome MT-, centrosome- and KT-dependent defects. Promising compounds will be tested for rescue in an array of complementary models including human cell lines and primary fibroblasts. 3DO will be generated as models carrying mutations in disease genes (e.g., PRUNE-1 and TUBA1A) to study mitotic defects rescued by newly identified drugs, aiming to dissect the genotype/phenotype correlation in NDDs. The results are expected to shed light on mitotic and cell division abnormalities impairing brain development. The project will be used in drug-screening platforms to provide a translational bridge between basic discoveries and potential therapies.

Goals

In this coordinated project, the task of the IBPM Unit Will focus on the implication of mitotic genes in neurodevelopmental disorders (NDDs), particularly microcephaly (MCPH) and tubulinopathies (TUB).

Our specific goals are to develop specific assays to assess the role of genes encoding the following products:
- the GTPase RAN and its effectors (RanBP1, importin beta) acting in nucleocytoplasmic transport;
- CENP-F and other kinetochore proteins in control of microtubule/kinetochore interactions;
- CASC5 (also known as KNL1/MCPH4), an essential kinetochore component that orchestrates the spindle assembly checkpoint function and chromosome segregation.

The overall goal is to understand the mechanisms and pathways operated by these factors, and their mutant versions identified in MCPH and TUB patients, to shed light on key mitotic events causing CNS disorders when dysfunctional.

Start date of activity

17/09/2019

Keywords

MOLECULAR GENETIX, developmental neruobiology, cell cycle and cell division

Last update: 05/07/2025