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Contribution of neuroplasticity in the rostral ventrolateral medulla to physical inactivity-related cardiovascular disease

Award Number: R01HL161233
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Physical inactivity is a major independent risk factor for cardiovascular disease (CVD) and is now considered the leading cause of premature death (Blair, 2009). Rates of physical inactivity continue to increase along with health care costs to treat CVD. Despite these disturbing trends, the mechanisms by which a sedentary lifestyle leads to CVD are not fully known. CVD is associated with increased sympathetic nervous system activity and overactivity of a brainstem region known as the rostral ventrolateral medulla (RVLM) (Sved et al., 2003;Guyenet, 2006). Sympathoexcitatory responses to direct activation of the RVLM are enhanced in sedentary versus physically active animals (Mischel and Mueller, 2011) and are associated with changes in dendritic branching (Mischel et al., 2014). These data suggest that a sedentary lifestyle may contribute to the development of CVD by increased sensitivity of RVLM neurons. Our long term goal is to understand the central sympathetic mechanisms by which physical inactivity contributes to the development of CVD. This is an important clinical, economic and public health care problem. The overall objective of this application is to define the mechanisms by which physical inactivity increases, and physical activity prevents over-activation of presympathetic neurons in the RVLM. Our central hypothesis is that sedentary and hypertensive conditions each enhance glutamatergic signaling, initiate BDNF-dependent mechanisms and further propagate enhanced glutamatergic signaling; such that in combination, produce clinically relevant increases in sympathetic outflow and blood pressure. This project is expected to shift current paradigms regarding the mechanisms by which physical inactivity and pro-hypertensive stimuli combine to increase sympathetic activity and exaggerate the hypertensive phenotype. We will test our central hypothesis in distinct but interrelated aims using our well- established models of sedentary or active conditions and 2K-1C hypertension with sham-operated rats as controls. Aim 1: Utilize in vivo gene targeting to determine the contribution of BDNF-TrkB signaling in sedentary and 2K1C mediated neuroplasticity in the RVLM. Aim 2: Establish relationships between BDNF and synaptic plasticity-associated mRNA and protein expression in the RVLM of sedentary versus active, normotensive and 2K1C rats using laser capture microdissection of presympathetic RVLM neurons and tract-tracing, triple- immunofluorescent labeling. Aim 3: Quantify glutamatergic tone and neuronal activity in the RVLM of sedentary versus active, normotensive or 2K1C rats using magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) of the RVLM. Our studies combine state-of-the art techniques with conceptually innovative hypotheses to fill significant knowledge gaps towards understanding two fundamentally important and intertwined, yet unresolved health problems, i.e. physical inactivity and hypertension.


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 = $560,283 )
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cardiovascular Diseases Research	000	3	11/22/2023	NON-COMPETING CONTINUATION	$560,283
														Subtotal = $560,283

Issue Date FY: 2023 ( Subtotal = $625,516 )
2023	2023	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cardiovascular Diseases Research	001	2	2/11/2023	NON-COMPETING CONTINUATION	$62,553
2023	2023	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cardiovascular Diseases Research	000	2	12/1/2022	NON-COMPETING CONTINUATION	$562,963
														Subtotal = $625,516

Issue Date FY: 2022 ( Subtotal = $647,463 )
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cardiovascular Diseases Research	000	1	11/24/2021	NEW	$647,463
														Subtotal = $647,463

Grand Total All Awards = $1,833,262

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Contribution of neuroplasticity in the rostral ventrolateral medulla to physical inactivity-related cardiovascular disease

Award Number: R01HL161233

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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