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Multimodal Optical Imaging on the Effect of Maternal Polysubstance Exposure on Fetal Brain Microvessel Function

Award Number: R01HD086765
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY The etiology of congenital brain growth anomalies is complex, but prenatal alcohol/ethanol and nicotine exposure (PEE/PNE) are common causal factors in the US and worldwide. Research has mainly focused on the growth deficits in neural stem cells (NSCs) and their progeny following PEE/PNE. However, we recently used high- resolution imaging to document that PEE results in complementary deficits in blood flow in major cranially- directed arteries. During the previous project period, we adapted Optical Coherence Tomography (OCT) to document that both PEE and PNE resulted in a similar loss of blood flow in the efferent peri-neural vascular plexus (PNVP). The PNVP and its companion, the sub-ventricular vascular plexus (SVP), give rise to capillaries that penetrate the parenchyma of the developing brain. In the NSC niche of the fetal ventricular zone (VZ) these give rise to an atypical class of fenestrated capillaries that contain 50-100 nm-sized trans-endothelial windows. The function of capillary fenestration in the fetal brain is unknown. Still, in the adult brain, the presence of fenestrated capillaries in selected circumventricular brain regions facilitates the transfer of systemic macromolecules into the brain, and persistent activation of brain microglia, and in residual neurogenic niches, facilitates neurogenesis. Based on preliminary and published data, we hypothesize that prenatal ethanol will increase brain angiogenesis, capillary fenestration, and microglial immune cell precursor trafficking to the fetal brain. We further hypothesize that prenatal nicotine will potentiate the alcohol-mediated increase in new blood vessel formation in the fetal brain and additively increase capillary permeability and immune cell migration into the NSC niche of the fetal VZ. To test these hypotheses, our team will develop a new sensitive, high-resolution imaging platform (Aim 1) that combines the complementary benefits of OCT and two-photon light-sheet microscopy (2pLSM) for in utero time-resolved structural imaging of fetal brain capillary micro-vessels with molecular specificity. We will also adapt our innovative intravital imaging technology and mouse reporter models to assess the effects of PEE and/or PNE on the dynamic growth of fetal VZ capillaries and their capacity to transfer macromolecules from fetal systemic circulation to the brain (Aim 2) and the adhesion and diapedesis of immune microglial cell precursors into the fetal NSC niche (Aim 3). This proposal will result in innovative high-resolution imaging tools for in utero fetal imaging and enable for the first time, dynamic, time-resolved assessment of capillary permeability and monocyte precursor invasion, to fill a significant gap in our understanding of the genesis of brain growth deficits due to PEE and/or PNE. These studies will also position us to begin to assess the efficacy of novel pharmacological intervention strategies targeted to prevent or reverse the effects of PEE and PNE on fetuses


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: 2024 ( Subtotal = $644,921 )
2024	2024	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Child Health and Human Development Extramural Research	000	8	8/26/2024	NON-COMPETING CONTINUATION	$644,921
														Subtotal = $644,921

Issue Date FY: 2023 ( Subtotal = $653,647 )
2023	2023	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Child Health and Human Development Extramural Research	000	7	7/21/2023	NON-COMPETING CONTINUATION	$653,647
														Subtotal = $653,647

Issue Date FY: 2022 ( Subtotal = $592,048 )
2022	2022	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Child Health and Human Development Extramural Research	001	6	9/14/2022	COMPETING CONTINUATION	$609,697
2022	2020	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Child Health and Human Development Extramural Research	000	5	8/22/2022	NON-COMPETING CONTINUATION	-$17,649
														Subtotal = $592,048

Issue Date FY: 2020 ( Subtotal = $345,824 )
2020	2020	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Child Health and Human Development Extramural Research	001	5	2/7/2020	NON-COMPETING CONTINUATION	$34,583
2020	2020	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Child Health and Human Development Extramural Research	000	5	12/16/2019	NON-COMPETING CONTINUATION	$311,241
														Subtotal = $345,824

Issue Date FY: 2019 ( Subtotal = $345,824 )
2019	2019	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Child Health and Human Development Extramural Research	000	4	12/24/2018	NON-COMPETING CONTINUATION	$345,824
														Subtotal = $345,824

Issue Date FY: 2018 ( Subtotal = $345,824 )
2018	2018	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Child Health and Human Development Extramural Research	001	3	5/1/2018	NON-COMPETING CONTINUATION	$34,583
2018	2018	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Child Health and Human Development Extramural Research	000	3	12/14/2017	NON-COMPETING CONTINUATION	$311,241
														Subtotal = $345,824

Issue Date FY: 2017 ( Subtotal = $345,824 )
2017	2017	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Child Health and Human Development Extramural Research	000	2	12/27/2016	NON-COMPETING CONTINUATION	$311,241
2017	2017	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Child Health and Human Development Extramural Research	001	2	6/20/2017	NON-COMPETING CONTINUATION	$34,583
														Subtotal = $345,824

Issue Date FY: 2016 ( Subtotal = $424,849 )
2016	2016	UNIVERSITY OF HOUSTON DOWNTOWN	ONE MAIN STREET	HOUSTON	TX	77002	HARRIS	USA	Child Health and Human Development Extramural Research	000	1	12/31/2015	NEW	$424,849
														Subtotal = $424,849

Grand Total All Awards = $3,698,761

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Multimodal Optical Imaging on the Effect of Maternal Polysubstance Exposure on Fetal Brain Microvessel Function

Award Number: R01HD086765

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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