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Molecular Neuro-pathogenesis of Congenital Cytomegalovirus Infection

Award Number: SC1AI112785
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/07/2014
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Molecular Neuro-pathogenesis of Congenital Cytomegalovirus Infection - PROJECT SUMMARY/ABSTRACT Human cytomegalovirus (HCMV) infection is the leading infectious cause of congenital disorders in newborns. Congenital HCMV infection causes permanent neurological and neurocognitive disabilities and results in significant health problems worldwide. Our preliminary findings reveal that Notch pathway is affected by HCMV infection and probably via interaction with CMV-encoded protein, IE1. Therefore, we propose to explore the molecular pathogenic mechanism via Notch pathway underlying abnormal brain development caused by congenital CMV infection. This proposed approach is fundamentally different from previous studies because we apply our unique technologies to explore the mechanisms that CMV employs to interfere with the brain development of embryos. We will apply the in vitro HCMV infection system, in utero electroporation system for mouse CMV (MCMV) gene delivery, conditional transgenic mouse model, and intraplacental MCMV infection system. Our long-term goal is to reveal the mechanisms underlying CMV-induced congenital neurodevelopmental disorders and develop potential anti-CMV therapeutics. We hypothesize that the coordinative interaction between CMV and Notch signaling is the key to causing developmental defects of infected neural progenitor cells (NPCs) in embryos, resulting in permanent neurological and intellectual disabilities. The hypothesis is supported by our preliminary data and publications from in vitro and in vivo experiments that HCMV infection affects Notch signaling, that Notch signaling is involved in CMV-caused defects of NPC proliferation, that IE1 is essential and sufficient to inhibit NPC proliferation, and that IE1 interacts with proteins of Notch signaling pathway. We will test our hypothesis via the following Specific Aims: Aim 1. To examine molecular mechanisms for how HCMV IE1 causes defects of human NSC/NPC proliferation and differentiation in cell culture; and Aim 2. To examine how the CMV IE1 causes different stages of neurogenic defect using an IE1-inducible transgenic mouse model and a clinically- relevant intraplacental MCMV infection mouse model. We believe that the present proposal is innovative in several points: First, this is one of the first studies that uses an inducible transgenic mouse model introducing a specific CMV protein, IE1, to address molecular mechanisms underlying congenital CMV infection. Second, we study the congenital CMV infection pathology from molecular levels to behavior levels. Lastly, investigators with different professional backgrounds (virology and neuroscience) are working together to address an important question with high medical impact. Positive impacts will include qualitative advances in understanding molecular virology and CMV pathobiology in particular, and that understanding the mechanisms CMV uses to cause neural defects may thus drive development of new, selective anti-CMV therapeutic strategies.


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 = $0 )
2026	2021	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	8	1/12/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	8	8/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	8	7/19/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $377,500 )
2021	2021	HOWARD UNIVERSITY (INC)	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	8	7/20/2021	NON-COMPETING CONTINUATION	$377,500
														Subtotal = $377,500

Issue Date FY: 2020 ( Subtotal = $377,500 )
2020	2020	HOWARD UNIVERSITY (INC)	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	7	7/22/2020	NON-COMPETING CONTINUATION	$377,500
														Subtotal = $377,500

Issue Date FY: 2019 ( Subtotal = $377,500 )
2019	2019	HOWARD UNIVERSITY (INC)	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	001	6	7/19/2019	NON-COMPETING CONTINUATION	$377,500
2019	2017	HOWARD UNIVERSITY (INC)	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	4	4/22/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $377,500

Issue Date FY: 2018 ( Subtotal = $377,500 )
2018	2018	HOWARD UNIVERSITY (THE)	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	001	5	8/7/2018	COMPETING CONTINUATION	$377,500
2018	2017	HOWARD UNIVERSITY (THE)	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	4	8/6/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $377,500

Issue Date FY: 2017 ( Subtotal = $332,200 )
2017	2017	HOWARD UNIVERSITY, INC.	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	4	3/24/2017	NON-COMPETING CONTINUATION	$332,200
														Subtotal = $332,200

Issue Date FY: 2016 ( Subtotal = $332,200 )
2016	2016	HOWARD UNIVERSITY	2244 TENTH STREET, NW ROOM 337	WASHINGTON	DC	20001	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	3	3/16/2016	NON-COMPETING CONTINUATION	$332,200
														Subtotal = $332,200

Issue Date FY: 2015 ( Subtotal = $332,200 )
2015	2015	HOWARD UNIVERSITY	2244 TENTH STREET, NW ROOM 337	WASHINGTON	DC	20001	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	2	4/8/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$332,200
														Subtotal = $332,200

Issue Date FY: 2014 ( Subtotal = $324,280 )
2014	2014	PONCE MEDICAL SCHOOL FOUNDATION INC	P.O. BOX 7004	PONCE	PR			USA	Allergy and Infectious Diseases Research	000	1	3/19/2014	NEW	$324,280
														Subtotal = $324,280

Grand Total All Awards = $2,830,880

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Molecular Neuro-pathogenesis of Congenital Cytomegalovirus Infection

Award Number: SC1AI112785

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/07/2014

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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