Education & Training
- Ph.D. in Molecular Biophysics & Biochemistry from Yale University, New Haven, CT, 1981
- B.A. in Biology from Temple University, Philadelphia, PA, 1976
Research Interest Summary
The life threatening, emotional and economic burdens of premature birth have been greatly alleviated by antenatal treatment with synthetic glucocorticoids (sGCs). While antenatal sGCs reduce respiratory distress syndrome, intraventricular hemorrhage and necrotizing enterocolitis in premature infants, they can affect developmental processes in the brain and trigger adverse behavioral and metabolic outcomes later in life. Therefore, there is an unmet clinical need to understand the mechanistic basis for sex- and race-specific effects of sGCs on the fetal brain and develop newer antenatal sGC therapies to reduce their potential adverse neurodevelopmental effects. The DeFranco lab seeks to identify novel genomic sGC targets that influence neural stem cell proliferation and differentiation. Experimental approaches include molecular and behavioral studies in mice as well as genome wide assessment of glucocorticoid receptor (GR) target genes. Of direct clinical relevance are proposed studies with cells derived from human fetuses that were exposed to antenatal GCs. Analogous approaches are also being utilized to examine the mechanisms for crosstalk in fetal brain between the GC and cannabinoid signaling pathways, which has been documented in adult brain. The results of these studies could be translated directly into new clinical guidelines regarding the use antenatal sGCs (e.g. altered dosing, enhanced risk of adverse neurodevelopmental effects in fetus) in women who abuse marijuana during pregnancy. The DeFranco lab also uses rodent models to study sGC responses in neonatal brain. sGC therapy (i.e. typically dexamethasone (Dex)) for neonates that develop bronchopulmonary dysplasia (BPD) carries significant concerns for not only short-term systemic side effects, but also detrimental impact on long-term neurodevelopment and structural brain development. As such, there remains a need for a GC therapy that will have the desired anti-inflammatory effect in neonatal lungs, but which would not produce negative systemic or neurological side effects triggered by current sGCs.
Samarasinghe RA, Di Maio R, Volonte D, Galbiati, F, Lewis M, Romero G, DeFranco DB (2011). Non-genomic glucocorticoid receptor action regulates gap junction intercellular communication and neural progenitor cell proliferation. Proc. Natl. Acad. Sci. USA 108, 16657-16662. PMID: 21930911
Indyk JA, Candido-Vitto C, Wolf IM, Venkatarman S, Munoz, R, Saladino RA, Witchel, SF, DeFranco DB (2013). Altered glucocorticoid signaling in children with critical illness: reduced glucocorticoid receptor protein expression and increased free cortisol concentration. Horm. Res. Pediatr. 79, 169-178. PMID: 23548248
Tsiarli MA, Monaghan-Nichols AP, DeFranco DB (2014). Differential subcellular localization of the glucocorticoid receptor in distinct neural stem and progenitor populations of the mouse telencephalon in vivo. Brain Research 1523, 10-27. PMID: 23751362
Peffer ME, Chandran UR, Luthra S, Volonte D, Galbiati F, Garabedian MJ, Monaghan-Nichols AP, DeFranco DB (2014). Caveolin-1 regulates genomic action of the glucocorticoid receptor in neural stem cells. Mol. Cell. Biol. 34, 2611-2623. PMID: 24777604
Samarasinghe RA, Kanuparthi PS, Greenamyre JT, DeFranco DB & Di Maio R (2014). Transient muscarinic and glutamatergic stimulation of neural stem cells trigger acute and persistent changes in differentiation. Neurobiol. Disease 70, 252-261. PMID: 25003306.
Peffer ME, Zhang JY, Umfrey L, Rudine AC, Monaghan AP, DeFranco DB (2015). The impact of antenatal therapeutic synthetic glucocorticoids on the developing fetal brain. Mol. Endocrinol. 29, 658-666. PMID: 25763611.
Frahm KA, Peffer ME, Zhang JY, Luthra S, Chakka AB, Couger MB, Chandran UR, Monaghan AP & DeFranco DB (2016). The dexamethasone transcriptome in hypothalamic embryonic neural stem cells. Molecular Endocrin. 30, 144-154. PMCID: PMC4695633
Tsiarli MA, Rudine A, Kendal N, Pratt MO, Krall R, Thiels E, DeFranco DB & Monaghan AP (2017). Antenatal dexamethasone exposure differentially affects distinct cortical neural progenitor cells and triggers long-term changes in cerebral architecture and behavior. Transl. Psychiatry 7, e1153. PMID: 28608856.
Frahm KA, Waldman JK, Luthra S, Rudine AC, Monaghan-Nichols AP, Chandran UR & DeFranco DB (2018). A comparison of sexually dimorphic dexamethasone transcriptome in mouse cerebral cortical and hypothalamic embryonic neural stem cells. Mol. Cell. Endocrinol. S0303-7207, 30295. PMID 28554804
Carson RA, Rudine AC, Tally SJ, Franks AL, Frahm KA, Waldman JK, Silswal N, Burale S, Phan JV, Chandran UR, Monaghan AP & DeFranco DB (2018). Statins impact primary embryonic mouse neural stem cell survival, cell death and fate through distinct mechanisms. PLoSONE, 13(5):e0196387. PMID: 29738536.
Franks AL, Berry KJ, DeFranco DB (2019). Prenatal drug exposure and neurodevelopmental programming of glucocorticoid signaling. J. Neuroendocrinol. e12786: PMID: 31469457.