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Mechanisms of aortopathy in LRP1 deficiency

Award Number: K08HL146893
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 12/10/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Mechanisms of aortopathy in LRP1 deficiency - Project Summary/Abstract Aortic dissection and aneurysmal disease accounts for over 10,000 deaths in the United States each year, and 1-2% of all deaths in Western countries. Consistent with prior studies that reveal that tight regulation of the TGFβ signaling pathways is essential for vascular development and the maintenance of the vessel wall, our preliminary data suggest overactivity of this pathway contributes to aortopathy. In addition, our preliminary proteomic data suggests activation of the PDGF pathway in two animal models of aneurysm and dissection. The Ucuzian lab, under the mentorship of Dr. Strickland, has utilized two murine models of aortic disease to identify several dysregulated pathways associated with aortopathy: 1) a smooth muscle cell specific LDL receptor-related protein 1 (LRP1) deficiency model; and 2) a lysyl oxidase (LOX) inhibition model using the drug -aminopropionitrile (BAPN). Exciting preliminary data by the Ucuzian and Strickland labs has identified a novel finding that mild aerobic exercise attenuates the aortopathy associated with both smLRP1 deficiency and LOX inhibition. The objectives of this proposal are to investigate the molecular mechanisms by which aneurysms and dissections develop, and to investigate exercise intervention to attenuate these processes. We will utilize both a mouse models of aortopathy and a human subject study to address these questions. Specific Aim 1. To define mechanisms underlying the development of aortic disease using two mouse models of aortopathy. The hypothesis is that smLRP1 and LOX protects against the development of aortic aneurysm and dissection by attenuating TGF and/or PDGF mediated signaling events. Specific Aim 2. To define mechanisms by which mild aerobic exercise attenuates the development of aortic disease using two mouse models of aortopathy. The hypothesis is that exercise prevents aortic aneurysm and dissection formation by attenuating TGF and/or PDGF mediated signaling events. Specific Aim 3. To identify dysregulated molecular pathways in patients presenting with ascending aortic aneurysms and Type A dissections. The primary hypothesis is that TGF signaling will be activated in human subjects presenting with thoracic aneurysms and dissections. The secondary hypothesis is that the presence of these pathway disturbances will correlate with the severity and extent of aortic disease presentation. The long-term goals of Dr. Areck Ucuzian, the trainee, is to become an independent physician-scientist in the field of Vascular Biology. His short-term goal is to cultivate the skills and experience required of a researcher to become an independent clinician-investigator. The current proposal focuses specifically on a fundamental mechanism of vessel wall homeostasis which prevents a broad range of vascular diseases. The Aims of this study are planned to be completed at the Center for Vascular and Inflammatory Diseases (CVID) and the University of Maryland, Baltimore (UMB) under the mentorship of Dr. Dudley Strickland, PhD.


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: 2025 ( Subtotal = -$22,238 )
2025	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	5	4/25/2025	NON-COMPETING CONTINUATION	-$22,238
														Subtotal = -$22,238

Issue Date FY: 2024 ( Subtotal = $163,188 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	5	11/6/2023	NON-COMPETING CONTINUATION	$163,188
														Subtotal = $163,188

Issue Date FY: 2023 ( Subtotal = $163,020 )
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	4	11/17/2022	NON-COMPETING CONTINUATION	$163,020
														Subtotal = $163,020

Issue Date FY: 2022 ( Subtotal = $163,020 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	3	12/20/2021	NON-COMPETING CONTINUATION	$163,020
														Subtotal = $163,020

Issue Date FY: 2021 ( Subtotal = $163,126 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	2	12/9/2020	NON-COMPETING CONTINUATION	$163,126
														Subtotal = $163,126

Issue Date FY: 2020 ( Subtotal = $163,188 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	1	12/6/2019	NEW	$163,188
														Subtotal = $163,188

Grand Total All Awards = $793,304

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Mechanisms of aortopathy in LRP1 deficiency

Award Number: K08HL146893

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 12/10/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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