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.