Spatiotemporal control of gene expression during embryonic development requires orchestrated activities of numerous enhancers. Proper activation of enhancers is critical not only for embryonic development, but also adult tissue homeostasis and regeneration; and inappropriate enhancer activity is often associated with pathological conditions such as cancer. Here we propose using mouse models to validate enhancers we recently identified using a new stem cell-based approach, and further developing new methods for large-scale functional interrogation of enhancer activities.
Unfit and yet viable cells are inevitably generated during animal development and growth. These viable unfit cells, if not removed, can compete with healthy cells for nutrients and space, generating sub-optimal tissues that negatively impact the health of animals. We aim to characterize a novel cell-intrinsic surveillance network that allows unfit cells to self-identify and self-destruct, a program ensuring animal fitness in a cell-autonomous manner.
Each time a cell divides it must produce accurate copies of its chromosomes to preserve the genetic information contained in the chromosomal DNA. This process, called DNA replication, is essential and defects in DNA replication can lead to the mutations and chromosomal rearrangements associated with developmental disorders and diseases, such as cancer. This project will generate novel assays and tools for the isolation and structural analysis of the large, multi-subunit, protein complexes mediating DNA replication in budding yeast cells to illuminate the mechanism of eukaryotic DNA replication.
Cross-linking mass spectrometry (XLMS) has emerged as a powerful tool to study protein structure in situ and in live tissues. Many proteins contain carboxylic acids on their surfaces, but it is currently difficult to cross-link these acids efficiently. We propose to develop a novel chemical reagent to enable efficient cross-linking of these acidic residues for use in XLMS.
The kynurenine pathway impacts major diseases such as major depressive disorder, Alzheimer’s, and cancer. Experiments in mice show that the gut microbiome modulates the kynurenine pathway, but the mechanism remains elusive. In this application we propose experiments where we damage the microbiota of mice using antibiotics, and use metabolomics to investigate the kynurenine pathway, together with computational analysis to determine how intestinal microbes impact the kynurenine metabolism.