# Mechanistic studies of Mas receptor activation and its role in aortic aneurysm formation

> **NIH NIH K08** · DUKE UNIVERSITY · 2020 · $150,063

## Abstract

PROJECT SUMMARY/ABSTRACT
 This proposal is a for a five-year research program for a future junior faculty member, Dr. James Wisler,
for studying cardiovascular cellular signaling under the mentorship of Dr. Robert Lefkowitz. Dr. Wisler is
currently in his fellowship training in Cardiovascular Medicine at Duke University Medical Center and plans to
further his scientific training in the laboratory of Dr. Lefkowitz. Dr. Lefkowitz has been a leader in the fields of
cellular signaling, and cardiovascular biology for nearly four decades and has a long track record of training
successful physician-scientists. The research and career development program devised will include
specialized instruction, attendance at local and national scientific meetings, and an advisory committee that will
broaden the training experience and help best prepare Dr. Wisler to obtain independent investigator funding by
the end of this award period. In preliminary studies, we have identified a novel mechanism of aortic aneurysm
development in murine models of both sporadic thoracic and abdominal aortic aneurysms as well as in a
murine model of Marfan Syndrome, an inherited disorder complicated by the development of aortic aneurysms.
These results suggest this pathway may have a more global pathogenic role in aneurysmal disease. This
signaling pathway is dependent on angiotensin type IA receptor signaling. In addition, this pathogenic signaling
cascade is negatively regulated by another G protein-coupled receptor (GPCR), the MAS receptor. Although
the MAS receptor was de-orphanized over a decade ago, controversy exists over the precise mechanisms of
activation and signaling mediated via this receptor. The aims of this proposed research are to: 1) to define the
transducer coupling and signaling profiles downstream of the MAS receptor; 2) to delineate the properties of
Mas receptor activation using biophysical approaches; and 3) to determine if Mas receptor signaling effects
aortic aneurysm formation. Our lab is in a unique position to answer these questions as we have unparalleled
expertise in the investigation of in vitro and in vivo GPCR biology. We expect these studies to result in
important insights into the molecular mechanisms of aortic aneurysm formation as well as how regulation of
these mechanisms might be exploited therapeutically via targeting of a novel, counter-regulatory receptor.

## Key facts

- **NIH application ID:** 9949483
- **Project number:** 5K08HL133488-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** JAMES W WISLER
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $150,063
- **Award type:** 5
- **Project period:** 2017-07-15 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949483

## Citation

> US National Institutes of Health, RePORTER application 9949483, Mechanistic studies of Mas receptor activation and its role in aortic aneurysm formation (5K08HL133488-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9949483. Licensed CC0.

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