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Pellino 1 as a Critical Therapeutic Target to Mitigate ZIKV-induced Postnatal Cognitive Dysfunction following Congenital Infection

Award Number: F31AI200193
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/03/2027
PERIOD OF PERFORMANCE END DATE: 03/02/2028

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Pellino 1 as a Critical Therapeutic Target to Mitigate ZIKV-induced Postnatal Cognitive Dysfunction following Congenital Infection - PROJECT SUMMARY Zika virus (ZIKV) is an arboviral flavivirus which evolved in recent years from a primarily self-limiting and mild febrile illness of adults to a teratogenic threat, causing severe pathology in neonates that persist through adolescence. Between 3,000 and 6,000 children were diagnosed with a condition termed Congenital Zika Syndrome (CZS), characterized by microcephaly, hypertonia, and cognitive and physical deficits, during an epidemic of ZIKV in Brazil between 2014 and 2016. Children with CZS continue to display infantile cognition and severe physical disability nearly a decade later. Thousands more children exposed congenitally to ZIKV during this period were normocephalic, yet cognitive deficits and differences have been documented in these children as well as they have grown. Though ZIKV currently circulates at low levels in tropical and subtropical environments, expansion of vector Aedes species mosquitoes into more moderate climates poses a threat for a new outbreak to develop amongst naïve populations. To date there are no therapeutics or preventatives available to protect future pregnancies from congenital or postnatal pathology, and the mechanism by which ZIKV infects the fetal brain and mediates these persistent postnatal symptoms is unknown. We have identified an E3 ubiquitin ligase Pellino 1 (Peli1) as an exacerbator of ZIKV-mediated pathology through immune system activation and promotion of ZIKV replication. Our laboratory has previously shown that knocking out Peli1 both in vitro and in vivo attenuates ZIKV titer, reduces inflammation, and prevents fetal intrauterine growth restriction (IUGR). We have also blocked Peli1-mediated NF-κB activation through a synthetically produced Smad-6 derivative, called Smaducin-6, to test its therapeutic potential at fetal timepoints. These data led us to develop the central hypothesis that Peli1 promotes ZIKV pathogenesis in the brain through promoting microglial NF- κB activation, accelerating neuronal apoptosis and leading to persistent postnatal cognitive dysfunction. To test this hypothesis, we propose to investigate the role of Peli1 in ZIKV-induced postnatal cognitive dysfunction and evaluate Smaducin-6 as a therapeutic treatment for ZIKV-induced postnatal cognitive dysfunction in mouse models. Through these aims, we will promote a first-of-its-kind prenatal therapeutic to mitigate the development of CZS and prevent postnatal pathology. To accomplish this F31 project, we have formulated a detailed training plan consisting of major elements such as mastery of flow cytometry, histology, and behavioral assays from on-site experts, presentation at scientific conferences, grantsmanship and scientific writing training, and enhancement of mentoring skills.


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 = $39,848 )
2026	2026	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	1	9/3/2026	NEW	$39,848
														Subtotal = $39,848

Grand Total All Awards = $39,848

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Pellino 1 as a Critical Therapeutic Target to Mitigate ZIKV-induced Postnatal Cognitive Dysfunction following Congenital Infection

Award Number: F31AI200193

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/03/2027

PERIOD OF PERFORMANCE END DATE: 03/02/2028

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