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

项目总结/摘要 此K99/R 00应用程序的目的是为Zachary克莱顿博士提供支持，这是一个有前途的职位， 他是道格拉斯·席尔斯博士实验室的博士研究员。这项额外的研究和培训将使他能够 成功转型为心血管（CV）领域的独立研究者 physiology.作为他提出的K99培训计划的一部分，他将学习新的技术技能， 和专业技能，并参加各种职业发展活动，包括那些将有助于 使他成为心脏肿瘤学和细胞衰老领域的领导者。他提出的项目寻求 研究细胞衰老在调节动脉功能障碍（即主要危险因素）中的作用， 用于CV疾病[CVD]）与常用化疗药物多柔比星（DOXO），首先在小鼠中（K99） 后来翻译成小鼠和人类（R 00）。衰老细胞在DOXO后在CV系统中积累 并且细胞衰老可能加剧动脉功能障碍的上游调节因子（即炎症和 氧化应激）。在强有力的初步数据的指导下，克莱顿博士将首先（目标1）确认DOXO导致 动脉功能障碍通过细胞衰老，利用互补的小鼠模型，他可以 全身清除衰老细胞。在国际专家的指导和技术培训下， 他是细胞衰老领域公认的专家，然后（目标2）进行创新的离体细胞培养 在血管细胞中进行实验，以确定细胞衰老在介导关键表型中的作用 潜在的动脉功能障碍，由DOXO处理小鼠的血浆诱发。在过渡到一个教师 克莱顿博士下一步（目标3; R 00）将首先通过小鼠对小鼠的实验， 血浆交换实验，以确定DOXO介导的动脉功能障碍是否可以转移 以及这种反应是否依赖于细胞衰老激活。接下来，他将 通过确定接受DOXO治疗的癌症患者的血浆在治疗中的作用，将他的发现扩展到人类。 在培养的血管细胞中促进动脉功能障碍相关的表型。总体而言，拟议的研究 有可能解决NHLBI的2个战略研究重点：1）研究新的病理生物学 CVD发病的重要机制; 2）确定降低癌症血管发病率的策略 幸存者拟议的项目将为未来可资助的研究提供机会，最终将 在该奖项的第4-5年提交了一份新的R 01。Seals博士（主要导师）是一位国际 公认的和NIH资助的科学家，在翻译CV研究中具有成功指导的悠久历史。 在他的指导和共同导师Judith Campisi博士的指导下，顾问团队成员Youngho博士 Bae，托马斯LaRocca，扫罗Villeda，Lavanya Kondapalli，Kamali Kimdar和生物统计学家Zhiying You博士， 博士克莱顿将能够成功地完成拟议的研究和培训计划，并过渡到一个 在一家顶级（R1）研究机构获得独立的、校外资助的终身职位。

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.