Paola Giusti, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Our lab studies the function of cyclin-dependent kinase 5 (Cdk5) in neuronal development and neurodegeneration. Recent evidence suggests an additional role for Cdk5 in synaptic plasticity and learning and memory. Cdk5 is activated through binding to its neuronal-specific activator p35. Studies up until this point have shown that neurotoxic conditions result in the cleavage of p35 into p25 in vitro and subsequent cell death. Moreover, overexpression of p25 in vitro and in vivo, have been associated with neuronal cell death and brain atrophy, suggesting that overactivation of Cdk5 by p25 is detrimental. We now have novel data that chemical induction of long-term potentiation (LTP) can generate p25 without resulting in cell death. The experiments outlined herein seek to address the relationship between p25 production through LTP induction and synaptic plasticity using both in vitro and in vivo studies. Additionally, we are generating a knock-in mouse model which expresses a mutant form of p35 that is resistant to calpain-mediated cleavage to better address the physiological functions of p35 and p25 in neurodegeneration, synaptic plasticity and learning and memory. These experiments have the potential of enhancing our understanding of the molecular events involved in neurodegeneration, synaptic plasticity and learning and memory, and could lead to the development of new therapies. [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant) In this project, the candidate proposes to construct the first comprehensive map of brain-specific chromatin interactions from fetal and adult brains. Generating high-quality and high-resolution datasets of chromatin interactions at these two time-points will facilitate the interpretation and prioritization of schizophrenia (SCZ) GWAS findings. First, we will identify brain-specific and developmentally-relevant chromatin interactions at a genome-wide level using Hi-C (resolution ~40 kb). Second, we will use these results to guide the targeted interrogation of chromatin interactions at individual SCZ GWAS loci using Capture Hi-C (resolution ~1kb). We will further integrate brain-specific information from sources such as CommonMind and psychENCODE in the hope to connect a subset of SCZ GWAS loci to specific genes. Third, we will integrate Hi-C, Capture Hi-C, and SCZ GWAS results to prioritize SNP-gene pairs, and will use STARR-seq (self-transcribing active regulatory region sequencing) assays to functionally characterize these and identify a direction of association. These are essential experiments for the interpretation of SCZ GWAS findings. In addition to the scientific benefits inherent in this work, this project also provides an extensive training program in statistical genetics and functional genomics for the candidate. The training plan augments Dr. Giusti-Rodríguez' neuroscience training with skills making, analyzing, and using omics data to enable her to follow-up SCZ genomic findings. Furthermore, this project will provide a wealth of preliminary data for a subsequent R01.