DESCRIPTION (provided by applicant): PROJECT SUMMARY Aortic aneurysm is a prevalent condition defined by excessive aortic growth and medial wall remodeling that can result in lethal dissection and rupture. Few effective pharmacological treatments exist for aneurysm, due in large part to an incomplete understanding of the mechanisms that underlie the disease. The goal of this proposal is to derive a more comprehensive understanding of the molecular events that belie thoracic aortic aneurysm progression, and in so doing identify and validate potential targets for novel pharmacological therapy. Preliminary in vitro and in vivo data indicate that interactions between angiotensin II, integrin, and transforming growth factor β (TGFβ) signaling are key molecular elements of aneurysm pathogenesis. The principal investigator, Dr. Sarah Parker, uses a genetic knock-in mouse model of Marfan syndrome (MFS) to study the context-dependent molecular mechanisms leading to dysregulated TGFβ signaling in thoracic aortic aneurysm. In the mentored phase of this proposal, Dr. Parker will use in vitro techniques to assess how of Integrin β3 (ITGβ3) overexpression, as occurs in MFS, impacts aspects of vascular smooth muscle cell physiology known to be altered in aortic aneurysm, and use novel mass spectrometry technologies (data independent acquisition MS) to identify pathogenic signaling components downstream of ITGβ3 that drive altered VSMC physiology (Aim 1). In the transition to the independent phase, Dr. Parker will identify how another signaling network, β-Arrestin 2 (βARR2) biased signaling by the Angiotensin II Type 1 Receptor (AT1R), contributes to dysregulated TGFβ signaling and altered mechanical properties of VSMCs that occur during aneurysm in MFS (Aim 2). Finally, Dr. Parker will integrate the findings in Aims 1 and 2 to test a unifying hypothesis that altered matrix sensing by ITGβ3 contributes to βARR2 biased signaling by AT1R both in vitro as well as in vivo in MFS mice, and further determine whether pharmacological manipulation of ITGβ3 and/or βARR2-biased signaling can attenuate aneurysm progression in MFS (Aim 3). Dr. Parker received her Ph.D. in Physiology from the Medical College of Wisconsin (MCW). She has subsequently completed the first three and a half years of her Post Doctoral fellowship at Johns Hopkins University under the collaborative mentorship of Dr. Harry (Hal) Dietz, a renowned clinician and expert in the medical genetics of connective tissue disorders and aortic aneurysm, and Dr. Jennifer Van Eyk, a premier expert in clinical cardiovascular proteomics. Building upon her established expertise in cardiovascular physiology and mass spectrometry-based proteomic techniques, this K99/R00 award will allow Dr. Parker to (1) develop informatics and computational skills for the analysis and interpretation of complex molecular data sets, (2) in collaboration with Dr. Megan McCain at the University of Southern California, develop an in vitro m...