Thursday, May 2, 2024
5/2/2024
IMPACT OF PRENATAL VITAMIN A DEFICIENCY ON CELL FATE ALTERATIONS IN ADULT AIRWAY HYPERRESPONSIVENESS ABSTRACT This project is focused on defining a novel mechanism for human disease. The research team includes experts in assay development, epigenomics, developmental biology, asthma genetics, systems biology, and population genetics. Our focus is on the Developmental Origins of Health and Disease (DOHaD), which links intrauterine perturbations to adult phenotypes. In general, this is pursued by testing whether heritable transcriptional regulatory (epigenetic) mechanisms are altered in offspring to allow a memory of past exposure (the cellular reprogramming model). Our new model is focused on perturbations occurring during cell lineage commitment, leading to an altered repertoire of cells in an adult organ (the cell fate model). While the cell fate model is supported by preliminary data and has major potential to mediate adult disease, it is currently very understudied, and would in fact be eliminated by the cell proportion adjustment techniques used in current epigenetic association or transcriptomic studies. This project seeks to establish whether the DOHaD field could benefit from considering the cell fate model in understanding developmental influences on adult phenotypes. We propose to test both the “cellular reprogramming” and the “cell fate” models using a mouse system. We will apply histopathological approaches to understand cell subtype composition of developing and developed organs and will add correlative phenotypic assays to link changes with lung function. We will perform genome- wide assays using our double fluorescent mice to refine our ability to detect cellular reprogramming and cell fate changes in developing airway smooth muscle cell in the lung, and will map the loci mediating the cell fate responses to prenatal vitamin A (retinoic acid) deficiency. The effect of genetic background differences will be tested to define how retinoic acid interacts with DNA sequence polymorphism to mediate cellular and phenotypic differences. We then will use the mouse information to test the possibility that the regulatory loci in the mouse genome are orthologous to those associating pulmonary functions in human genome-wide association studies (GWAS). In this way, we can generate novel mechanistic insights into how genomic regions associated with pulmonary function variability mediate their effects, providing an excellent example of how to study gene x environment interactions.
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