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Characterizing the novel activity of THC directly at the androgen receptor on masculinization of the brain

Award Number: F30DA065321
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/21/2026
PERIOD OF PERFORMANCE END DATE: 02/20/2029

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Characterizing the novel activity of THC directly at the androgen receptor on masculinization of the brain - Project Summary The brain's development is a complex interplay among the nervous, endocrine, and immune systems. Disruption of any of these systems can disturb the delicate balance of normal neurodevelopment, increasing the risk of neuropsychiatric diseases later in life. The developing brain is characterized by its sensitivity to gonadal steroid hormones, particularly androgens produced by the fetal testis during the perinatal period. The surge of androgens from the fetal testis establishes the critical period of masculinization, during which androgen-sensitive brain regions undergo morphological and functional changes to prepare males for appropriate behaviors later in life, such as mating and aggression. The ability of androgens to organize neural substrates depends on the direct or indirect activity of the androgen receptor. The androgen receptor is a nuclear steroid receptor capable of binding to the promoter regions of specific genes, many of which function as epigenetic modifiers to alter transcriptional regulation. In addition to these direct effects, the androgen receptor has been shown to recruit the immune system through cannabinoid signaling to promote the masculinization of androgen-sensitive brain regions. The relationship between androgens and endocannabinoids creates a delicate balance during neurodevelopment, as endocannabinoids are potent regulators of neuroimmune molecules involved in homeostasis and pathology. With recent changes in legalization and shifts in cultural perspectives on cannabis, there has been an increase in cannabis consumption during pregnancy, which has been associated with a heightened risk of neuropsychiatric disease in offspring, possibly due to the disruption of the delicate endocannabinoid system recruited by androgens. However, our recent work highlights an additional and direct role of cannabis, primarily its psychoactive component 9-tetrahydrocannabinol (THC), in disrupting androgen-mediated brain development. We demonstrate in silico that THC can bind to the androgen receptor with an affinity similar to that of testosterone, thereby creating the potential to directly affect brain development through actions at the androgen receptor. This proposal seeks to characterize this novel and unexplored action of THC through advanced structural and genomic techniques. In Aim I, I will characterize the binding kinetics of THC at the androgen receptor through surface plasmon resonance and identify ligand-induced conformational changes to the ligand binding domain of the androgen receptor through NMR spectroscopy. In Aim II, I will differentiate the effects of THC and testosterone on androgen receptors in regulating transcription within androgen-sensitive brain regions through ATAC-seq. These findings will highlight a previously uncharacterized role of THC and provide greater insights into the mechanisms through which gestational cannabis exposure alters normal androgen- mediated neurodevelopment and how it may contribute to the susceptibility of offspring to neuropsychiatric diseases later in life. Scientific mentorship from Drs. McCarthy, Weber, and Ament will provide me with unparalleled training to support a future career as a clinician-scientist in the field of child neurology.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $48,866 )
2026	2026	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	1	2/6/2026	NEW	$48,290
2026	2026	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	002	1	3/25/2026	NEW	$576
2026	2026	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	001	1	2/6/2026	NEW	$0
														Subtotal = $48,866

Grand Total All Awards = $48,866

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Characterizing the novel activity of THC directly at the androgen receptor on masculinization of the brain

Award Number: F30DA065321

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/21/2026

PERIOD OF PERFORMANCE END DATE: 02/20/2029

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