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Role of the prorenin receptor in blood pressure and autonomic control through the local activation of the renin angiotensin system in the brainstem

Award Number: K01HL153101
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/20/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Role of the prorenin receptor in blood pressure and autonomic control through the local activation of the renin angiotensin system in the brainstem - PROJECT SUMMARY/ABSTRACT Hypertension affects nearly half of the population and it is the principal risk factor for heart attack and stroke, the leading first and third cause of death in the United States. The renin-angiotensin system (RAS), is one of the most studied mechanisms of blood pressure control. The classical view of the RAS involves a sequential cleavage of the substrate angiotensinogen resulting in the elevation of circulating angiotensin II (ANG). In addition to functioning within the circulation as a classical (endocrine) hormone system, several tissues including the brain produce local acting ANG, supporting the concept that autocrine/paracrine/intracrine versions of the RAS act locally within these tissues. However, this scientific premise has been challenged due to the difficulties to detect renin in extrarenal organs. Indeed, the enzymes catalyzing the hydrolytic removal of the prosegment, which is required for the activation of renin, are absent in extrarenal tissues. Utilizing cutting edge molecular techniques with superior specificity and sensitivity we were able to identify specific cells located in the rostral ventrolateral medulla (RVLM) that express renin. We also observed that in a model of neurogenic hypertension, such as mice lacking the alternative renin isoform (renin-b), there is a disinhibition of the classical renin isoform (renin-a) encoding preprorenin within the RVLM. This data has been our driving force to interrogate what is the function of renin- expressing cells within the RVLM, and moreover, are these cells initiating ANG signaling within the areas adjacent to the RVLM by secreting prorenin to the extracellular space which is abundant of angiotensinogen? A key step to answer these questions is to decipher how prorenin is activated. The discovery of prorenin receptor (PRR), a receptor that binds prorenin and induces its activation without the cleavage of the prosegment, might be a key player to solve this problem. In the recent years, several ANG-independent and (pro)renin-independent functions of PRR have been demonstrated. Since then, the role of PRR mediating the local activation of the RAS has been questioned. Given the long-held controversy in this field, our fundamental goal is to clarify the physiological and molecular role of PRR within the RVLM and then to dissociate the actions that are dependent of the RAS versus those that are independent of the generation of ANG. Finally, we propose a transcriptomic approach to identify the neuronal and molecular signature of the renin-expressing cells within the RVLM. Collectively, this project will facilitate continued technical, intellectual, and professional training for the candidate, and assist in the establishment of an independent research laboratory at an academic research institution.


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 = -$596 )
2026	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	5	1/15/2026	NON-COMPETING CONTINUATION	-$596
														Subtotal = -$596

Issue Date FY: 2024 ( Subtotal = $112,479 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	5	7/26/2024	NON-COMPETING CONTINUATION	$112,479
														Subtotal = $112,479

Issue Date FY: 2023 ( Subtotal = $112,479 )
2023	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	4	8/16/2023	NON-COMPETING CONTINUATION	$112,479
														Subtotal = $112,479

Issue Date FY: 2022 ( Subtotal = $112,479 )
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	3	7/20/2022	NON-COMPETING CONTINUATION	$112,479
														Subtotal = $112,479

Issue Date FY: 2021 ( Subtotal = $112,479 )
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	2	8/13/2021	NON-COMPETING CONTINUATION	$112,479
														Subtotal = $112,479

Issue Date FY: 2020 ( Subtotal = $112,479 )
2020	2020	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cardiovascular Diseases Research	000	1	8/20/2020	NEW	$112,479
														Subtotal = $112,479

Grand Total All Awards = $561,799

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Role of the prorenin receptor in blood pressure and autonomic control through the local activation of the renin angiotensin system in the brainstem

Award Number: K01HL153101

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/20/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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