NIH grant: Developmental reprogramming by gene environment interactions (1R21HD119634-01A1)

retained text

NIH grant 1R21HD119634-01A1: Developmental reprogramming by gene environment interactions
Institute: {'code': 'HD', 'abbreviation': 'NICHD', 'name': 'Eunice Kennedy Shriver National Institute of Child Health and Human Development', 'admin_org_id': '12500030', 'admin_funding_url': ''}. PI: Heidi  Lempradl. Award: $528000.
Start: 2026-08-01T00:00:00.
PROJECT SUMMARY
The Developmental Origin of Health and Disease (DOHaD) hypothesis postulates that parental environments
alter in utero or early development to influence offspring health later in life. Particularly the maternal metabolic
“state” is tightly linked to embryonic development, but the molecular mechanisms that link maternal metabolism
to offspring development (and health) are still unclear. Unfortunately, it is not possible to establish a causal,
mechanistic link between a mother’s metabolic “state” and her offspring’s developmental path or future health in
humans. We therefore use Drosophila as a “closed” model system and high throughput model to detect such
links. Once identified we try to confirm our findings in a mammalian model system. We recently identified an
interaction between dom/SRCAP haploinsufficiency and maternal obesity. SRCAP is encodes for a DNA-
dependent ATPase that replaces histone 2A (H2A) with a H2A.Z variant. In humans, some truncating SRCAP
mutations lead to Floating-Harbor syndrome (a neurodevelopmental disorder), while other loss-of-function
mutations are linked to autism spectrum disorder. A recently published mouse model showed that SRCAP
haploinsufficiency results in a neurodevelopmental phenotype that can be rescued by the expression of one of
the targets of H2A.Z37. Our preliminary findings lead to a working hypothesis that maternal obesity exacerbates
the effects of SRCAP haploinsufficiency, thereby altering early neuronal development. In two specific aims we
will 1) establish the mechanistic basis for SRCAP x maternal obesity interactions in Drosophila, and 2) identify
embryonic changes triggered by SRCAP x maternal obesity interactions in mice. We will use novel
methodologies such as low input epigenomics and single-embryo transcriptomics to identify the molecular
signatures during the earliest stages of development. Once completed, this project is expected to (i) uncover
critical insights into the developmental programs affected by the truncation of SRCAP and maternal obesity, both
individually and in combination; (ii) help establish how SRCAP and maternal obesity together reprogram
embryonic development in both Drosophila and mouse; and (iii) yield the first direct and mechanistic evidence
linking genetic susceptibility with maternal obesity, a modifiable risk factor with widespread implications for
maternal and child health.

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