Translational studies of cellular senescence as a regulator of doxorubicin-mediated arterial dysfunction

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PROJECT SUMMARY/ABSTRACT The purpose of this K99/R00 application is to provide support for Dr. Zachary Clayton, a promising post- doctoral fellow in the laboratory of Dr. Douglas Seals. This additional research and training will allow him to successfully transition into an independent investigator in the field of translational cardiovascular (CV) physiology. As part of his proposed K99 training plan, he will learn new technical skills, enhance his intellectual and professional skills and participate in various career development activities, including those that will help establish him as a leader in the fields of cardio-oncology and cellular senescence. His proposed project seeks to investigate the role of cellular senescence in regulating arterial dysfunction (i.e. the primary risk factor for CV diseases [CVD]) with the common chemotherapeutic agent Doxorubicin (DOXO), first in mice (K99) and later translating to mice and humans (R00). Senescent cells accumulate in the CV system following DOXO and cellular senescence may exacerbate upstream regulators of arterial dysfunction (i.e. inflammation and oxidative stress). Guided by strong preliminary data, Dr. Clayton will first (Aim 1) confirm that DOXO causes arterial dysfunction via cellular senescence by utilizing complementary mouse models in which he can systemically clear senescent cells. With guidance and training in technical skills from an internationally recognized expert in cellular senescence, he will then (Aim 2) conduct innovative ex vivo cell culture experiments in vascular cells to determine the role of cellular senescence in mediating key phenotypes underlying arterial dysfunction, evoked by plasma from DOXO-treated mice. After transitioning to a faculty position, Dr. Clayton will next (Aim 3; R00) translate his findings first to mice, by performing mouse-to-mouse plasma exchange experiments to determine whether DOXO-mediated arterial dysfunction can be transferred via the circulation and whether this response is dependent upon cellular senescence activation. Next, he will extend his findings to humans by determining the role of plasma from DOXO-treated cancer patients in facilitating arterial dysfunction-related phenotypes in cultured vascular cells. Overall, the proposed research has the potential to address 2 strategic research priorities of NHLBI: 1) investigate new pathobiological mechanisms important to the onset of CVD; 2) determine strategies for reducing vascular morbidity in cancer survivors. The proposed projects will provide opportunities for future fundable research, culminating in submission of a novel R01 during years 4-5 of this award. Dr. Seals (primary mentor) is an internationally recognized and NIH funded scientist with a strong history of successful mentoring in translational CV research. With his guidance and the guidance of co-mentor Dr. Judith Campisi, advisory team members Drs. Youngho Bae, Thomas LaRocca, Saul Villeda, Lavanya Kondapalli, Kamali Kimdar and biostatistician Dr. Zhiying You, Dr. Clayton will be able to successfully complete the proposed research and training plan and transition to an independent, extramurally-funded tenure-track position at a top-tier (R1) research institution.