THE CENTER  FOR HUMAN

DISEASE MODELING

Core Research Projects

1. Cilia and Ciliopathies

Our group has had a long-standing interest in a group of pediatric disorders caused by defects in cilia and their anchoring structure, the basal body. We have engaged broadly in gene discovery, pathway analysis, and the persistently challenging dissection of epistatic analyses in human patients and its role(s) in modulating variable penetrance and expressivity. We have continued our work through the implementation of a variety of interdisciplinary tools that include whole-exome and targeted resequencing of the ciliary proteome, cell-based analyses of ciliary functions and animal models of all ciliopathies that include transient manipulations in zebrafish embryos as well as mouse and zebrafish mutants.

 

2. Systematic Functionalization of the Morbid Pediatric Genome

Through a combination of in vitro and in vivo studies, we are moving towards generating physiologically-relevant assays for the majority of the known human pediatric morbid genome, namely the complement of ~1000 human genes causally associated with pediatric genetic disorders. Coupled to that effort is the generation and characterization of large allelic series of variants found in these genes both in pediatric patients as well as the general population.

 

3. Genetics and Cell Biology of Neurodevelopment Traits

As part of our broader interests in pediatric disorders, we have identified methods to query fundamental biological processes affected in children and infants with neurocognitive defects. Coupling gene identification with modeling of genetic lesions in model organisms, we are engaged in understanding how genes causally implicated in neurocognitive traits regulate neurogenesis, cell fate specification, migration and synaptogenesis.

 

4. Taskforce for Neonatal Genomics

Our Center leads a broad interdisciplinary initiative that encompasses several basic science departments including the Center for Human Genetics, the Institute for Genome Sciences and Policy and the Department of Cell Biology with several clinics, coordinated through the Neonatal and Perinatal Research Institute. The goals of this Unit is to bring together genomics, genetics, functional studies, and ethics to generate and interpret genomic data to assist physicians in diagnosis and patient management. Our primary focus is on neonates, infants and young children with anatomical defects of unknown causality.

 

5. Development of therapeutic paradigms

As part of our discovery activities, the Center has developed physiologically relevant in vivo models for several hundred pediatric disorders. In parallel, the Center has pursued the use of biologics as a means of lead compound discovery with therapeutic potential. Bringing the two together, we are interested in screening suitable in vivo models with small molecules to accelerate the discovery of promising lead compounds.