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Screening and validation of miRNA targets for neurogenic hypertension.

Award Number: R35HL184169
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/06/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2033

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Screening and validation of miRNA targets for neurogenic hypertension. - Program Summary With prevalence as high as 55% in individuals aged 55 and older in the United States, hypertension (HTN) is a major risk factor contributing to cardiovascular diseases and global mortality, hence remaining an increasingly important medical and public health issue. Despite the abundance of antihypertensives, only a small fraction of patients has their blood pressure (BP) under control. Neurogenic HTN is more difficult to treat, makes up a larger percentage of patients with resistant HTN, and the failure of antihypertensive therapy in these patients has been attributed to increased sympathetic outflow from the central nervous system. Our laboratory has been engaged in elucidating the role of the brain renin-angiotensin system (RAS), notably components of the compensatory RAS in the development of neurogenic HTN, for over two decades. These efforts resulted in the discovery of a compensatory role for Angiotensin (Ang) converting enzyme 2 (ACE2) as well as key post-translational modifications mechanisms limiting ACE2 compensatory activity in HTN. Notably, our group was the first to demonstrate the involvement of ADAM17 in the shedding of ACE2 and how this mechanism impairs ACE2’s ability to cleave Ang-II in experimental models of neurogenic HTN and patients. Another key mechanism, identified by our group, was ubiquitination which promotes internalization and degradation of ACE2. More recently, we identified two major E3 ligases, Nedd4-2 and UBR1, involved in the ubiquitination of ACE2. These studies have led to the description of GABAergic neurons in which ACE2 supports the inhibitory input to the paraventricular nucleus (PVN) of the hypothalamus, a key hub harboring pre-sympathetic neurons involved in the development of neurogenic HTN, as well as redundant mechanisms promoting ubiquitination and the loss of ACE2 compensatory activity. Furthering our understanding of the regulatory mechanisms affecting the brain RAS, we recently identified several miRNA that are differentially expressed in the hypothalamus of hypertensive mice from both sexes, some of which we have already validated as targeting RAS components and reducing the development of neurogenic HTN (e.g., miR-410-3p). However, this extensive list of miRNA needs to be refined based on regional relevance (i.e., nuclei related to BP regulation versus others) prior to systematically embarking in targets validation, gain/loss of function studies and assessment of the mimics/antagomirs’ therapeutic potential. Taking advantage of a spatial transcriptomics miRNA platform, we now can map those miRNAs to specific neuronal populations within the PVN and other important regions for BP regulation, to determine their relevance prior to assessing their therapeutic potential. We believe our studies would identify novel therapeutic targets to prevent resistant HTN, which may also have relevance in other cardiovascular diseases, such as heart failure. The long-term funding and flexibility of the R35 mechanism will help me to continue to train a new generation of scientists interested in studying neuro-cardiovascular dysfunction to develop novel therapies for neurogenic HTN.


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 = $1,008,719 )
2026	2026	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	000	1	4/7/2026	NEW	$1,008,719
														Subtotal = $1,008,719

Grand Total All Awards = $1,008,719

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Screening and validation of miRNA targets for neurogenic hypertension.

Award Number: R35HL184169

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/06/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2033

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