Project Details
Description
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.
Status | Finished |
---|---|
Effective start/end date | 4/1/20 → 3/31/24 |
Funding
- National Heart, Lung, and Blood Institute: $403,402.00
- National Heart, Lung, and Blood Institute: $413,663.00
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