The central goal of this Program Project is to address the central mechanism of human structural brain defects (SBD), utilizing the unique strengths of the Principal Investigators (PIs) and the new breakthroughs in genetics and modeling. This Program Project Grant is designed to advance biomedical knowledge and make a high impact on our understanding of the basis of SBDs across the evolutionary scale, with the purpose of advancing our ability to diagnose and treat disease. In our preliminary data, we have established:
- A broad database consisting of over 1500 human families with structural brain defects, highly enriched for first cousin consanguinity with multiple affected members.
- Extensive development of mouse lines with neural-specific expression of Cre-recombinase.
- A broad array of tools to study gene requirements in zebrafish development.
- A proven track record of utilization of these unique reagents to study mechanisms of disease.
As a result of our preliminary data, we have formulated this PPG with a two-fold thrust:
- By taking advantage of the technical revolution in DNA sequencing and genetic engineering, we will uncover new causes of disease in humans.
- By comparing phenotypes across these unique systems, each with its own strength/weakness, we will enhance our understanding of the basic mechanisms of SBD. Since all Pis in this PPG has evidence for considering cell polarity as central to the developmental mechanisms of SBD, each Project has a focus on investigating cell polarity within the spectrum of the proposed aims.
Two Cores will be essential to the PPG since they will carry out essential functions of the PPG and benefit each Project:
- Next-generation Sequencing Core to uncover new genetic causes of SBDs in each species.
- Bioinformatics Core will provide essential functions to provide experimental design and analytical services with one-on-one training and data management and custom computational solutions.
Specific Aims of the PPG are:
- To uncover a host of new developmental causes of SBD from this unique human DNA resource, as well as from mutagenized mice and zebrafish.
- To explore cell-type specificities of disease and pathogenic mechanisms of SBDs using mice and zebrafish models.
- To utilize newly uncovered mice and zebrafish genes involved in SBDs for analysis in this human population. We believe that this PPG will have a major impact on our understanding of the cellular and molecular mechanisms that underlie a variety of SBDs, fully taking advantage of new breakthroughs in genomics technologies, which will set the stage for improved diagnosis and treatment.