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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R00ES033257&format=word)
| Principal Investigator: Everman, Elizabeth | |
|---|---|
| Institute Receiving Award | University Of Oklahoma |
| Location | Norman, OK |
| Grant Number | R00ES033257 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 01 Sep 2023 to 31 Aug 2026 |
| DESCRIPTION (provided by applicant): | Contact PD/PI: Everman, Elizabeth PROJECT SUMMARY Heavy metal pollution has pervasive environmental, health, and evolutionary impacts. In humans, health risks of heavy metals ranging from permanent neurological disease to increased morbidity of degenerative syndromes are exacerbated by poverty and fragile community infrastructure. Physiological responses to heavy metals including lead, cadmium, and copper have complex genetic architectures, and several heavy metals are known to hinder learning and alter behavior. However, these behavioral and physiological responses to metal stress are often considered in isolation, neglecting the specific genetic relationship between metal toxicity and behavioral response to metal stress. My primary objective is to dissect and characterize this whole organism heavy metal response by taking an integrative approach to examine the genetic basis of the relationship between physiological, behavioral, and evolutionary responses to heavy metal stress. The elite genetic model Drosophila melanogaster is ideal for my research because it shares many heavy metal-responsive genes with humans, it is extremely facile to conduct large-scale phenotyping assays, and an enormous plethora of sophisticated tools are available to facilitate in-depth behavioral and genomic experiments. I treat copper as my model heavy metal because, although required at low levels for normal development and physiological function, it is a common heavy metal pollutant that is metabolized and bioaccumulated by genes that also interact with lead, manganese, zinc, and cadmium. With Aim 1, I will disentangle the genetic link between physiological and behavioral responses to copper stress using a large mapping panel of genetically stable strains and combining large-scale screens of multiple behavioral traits with physiological data collected across multiple life stages. With Aim 2, I will characterize genetic and coevolutionary responses to copper selection in multiple populations derived from high and low copper resistance natural populations. Aim 2 will involve an evolve and resequencing (E&R) approach coupled with bulk RNA barcoding and sequencing (BRB-seq) to track the dynamic shifts in allele frequencies and gene expression through the course of artificial selection for copper resistance. Investigation of the evolutionary processes that lead to complex trait variation has great biomedical significance as we seek to understand the gene-by-environment interactions, genetic constraints, and genetic risk factors that contribute to increased susceptibility to toxic heavy metal exposure in human populations. This integrative approach leverages QTL mapping, whole genome and RNA-seq, sophisticated functional validation tools available for the D. melanogaster model system, and experimental evolution. This work will ultimately allow for the characterization of genetic variation in chemosensory ability, traits related to decision making, and neurological function in response to copper stress in diverse synthetic and naturally derived genetic backgrounds. Together, these approaches will provide critical insight into the interconnectedness of multiple response traits, while also illuminating genetic factors that influence behavioral and learning disabilities linked to metal poisoning. |
| Science Code(s)/Area of Science(s) |
Primary: 60 - Nervous System Research Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | No publications associated with this grant |
| Program Officer | Kimberly Mcallister |