[K08] Colon cancer mediates arterial remodeling through smooth muscle cell phenotypic changes via PDGFR-B signaling

Ente: National Heart Lung and Blood Institute

Scadenza: 2031-06-30

Importo max: 163.285 EUR

Paese: US

Descrizione

ABSTRACT Cardiovascular disease (CVD) and cancer remain the leading causes of death globally and are increasingly co-prevalent in aging patients. Extensive population-level evidence demonstrates that patients with cancer have significantly increased cardiovascular morbidity and mortality, and, conversely, patients with CVD have significantly increased risk of incident cancer. The bidirectional associations extend beyond simple shared risk factors and cardiotoxicity from cancer therapies to include shared molecular mechanisms and disease cross- communication, both of which are poorly defined. This K08 career development award is designed to launch the principal investigator’s career as an independent physician-scientist that utilizes complementary animal modeling, molecular, and computational approaches to define mechanisms connecting CVD and cancer, then translates these findings into treatments. The principal investigator’s primary mentor Dr. Timothy McKinsey is a leader in epigenetic and signaling mechanisms driving cardiovascular remodeling and fibrosis. The proposed training is further supplemented by co-mentors with expertise in vascular smooth muscle cell (VSMC) biology, cardio-oncology, cancer-vascular crosstalk, bench to bedside translation, and computational genomics. Didactic courses at the University of Colorado Anschutz Medical Center (AMC) and Cold Spring Harbor Lab will also be leveraged to augment technical training and career development. AMC serves as a vibrant training environment with robust cardiovascular and cancer research programs and resources, and has provided the principal investigator with significant protected time and start-up funds to achieve her goals on this campus. Funded by a Damon Runyon Physician-Scientist training grant, the principal investigator previously used a combination of in vivo and in vitro models demonstrating significant VSMC plasticity in the tumor microenvironment of colorectal cancer (CRC). In line with the real-world observation that CRC patients have higher rates of hypertension during treatment and in survivorship, preliminary studies suggest that CRC also has a broader impact on more distant blood vessels mediated by PDGF-B secretion and PDGFRβ VSMC dedifferentiation signaling. The proposed study will: (1) define the mechanical and physiologic vascular parameters changed by the presence of CRC; (2) define the epigenetic and signaling VSMC changes induced by the presence of CRC; (3) determine shared genetic risk for vascular remodeling and CRC. The result of this study will elucidate how CRC interacts with the broader vascular system and if there are inherited modulators of risk for both diseases. Additionally, the principal investigator will gain the training needed to transition into an independent physician-scientist focusing on translating clinical observations of cardiovascular sequelae in cancer patients into specific mechanisms and novel interventions. Istituzione: UNIVERSITY OF COLORADO DENVER PI: Caitlin Fox Bell Progetto: 1K08HL181477-01A1

Settori: National Heart Lung and Blood Institute

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