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Dan Gorelick Lab

Projects

Master
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Estrogens and Heart Development

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Estrogens are essential hormones for the development and function of the reproductive tract. Estrogen signaling also plays a critical role in non-reproductive tissues, such as the heart. We found that estrogens regulate heart rate via the G protein-coupled estrogen receptor (GPER), independent of canonical nuclear estrogen receptors. We are working on identifying the specific signaling pathways by which GPER regulates heart rate. Humans are exposed to structurally diverse estrogens through diet, pharmaceuticals and aquatic contamination. Using zebrafish, we are testing the effects of environmental estrogens on heart rate. Our results may identify a mechanism underlying the association between increased estrogen levels, higher resting heart rate and incidence of cardiac arrhythmia in humans

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Sex Determination and Differentiation

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Zebrafish exhibit unique sex determination and differentiation mechanisms. All juvenile zebrafish contain a bipotential gonad that appears histologically as an immature ovary. In female zebrafish this bipotential gonad matures into a functional ovary, whereas in males the bipotential gonad regresses and is replaced by a testis. The signals that determine whether a juvenile, bipotential gonad develops into testes or ovaries are not well understood. We found that the nuclear androgen receptor is critical for proper organization of the testes and for oocyte development in ovaries. Androgen receptor mutants exhibit a female sex bias with altered secondary sex characteristics. In contrast, the non-canonical G protein-coupled estrogen receptor appears to be dispensable for proper ovary differentiation and function. Current work in the lab is focused on investigating the signaling pathways by which androgens & estrogens influence testes organization and oocyte development.

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Aryl Hydrocarbon Receptor Signaling

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Exposure to byproducts of industrial combustion, such as polycyclic aromatic hydrocarbons (PAH) causes multi-organ phenotypes. Understanding the signaling pathways by which such compounds cause toxicity is crucial for predicting acceptable exposure levels and for reversing the effects of adverse exposure. PAHs activate aryl hydrocarbon receptors (AHR), ligand-dependent transcription factors that recruit cofactors to DNA and directly regulate gene expression. However, our knowledge of AHR cofactor recruitment and regulation is limited. We are identifying AHR cofactors required for PAH-dependent cardiotoxicity. Using genetic approaches, we will test whether candidate cofactors are required for PAH cardiotoxicity. We will also use unbiased biochemical and proteomic approaches to purify PAH-AHR protein complexes from the developing heart and identify interacting proteins.

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Dolutegravir and Birth Defects

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Dolutegravir (brand name Tivicay) is an antiretroviral medication used to treat HIV. Recent studies show an increased prevalence of neural-tube defects in infants born to women using dolutegravir exposure compared to women taking other antiretroviral medications (Zash et al, NEJM 2019; Raesima et al, NEJM 2019). Our colleagues Drs. Richard Finnell and Robert Cabrera hypothesized that dolutegravir could be causing neural tube defects by interfering with folate signaling. We found that zebrafish embryos exposed to dolutegravir develop abnormally. Co-exposure to folate rescued these abnormalities. Our results suggest that dolutegravir causes neural tube defects by blocking folate signaling. Current research questions include: what specific defects in zebrafish embryonic development are caused by dolutegravir? In which cells does dolutegravir act to cause toxicity in zebrafish embryos? What genes and molecular and cellular pathways are abnormal following dolutegravir exposure? Is there a critical window of development when dolutegravir is most toxic? Do other antiretroviral medications, besides dolutegravir, cause developmental defects in embryos?