权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Investigating the role of apoptosis regulation in cancer therapy-induced vascular toxicities

研究细胞凋亡调节在癌症治疗引起的血管毒性中的作用

基本信息

批准号：
10537996
负责人：
Mary Heather Celine Florido
金额：
$ 3.89万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10537996
关键词：
ARHGEF5 gene Acute Adolescent Adult Affect Aftercare Age Aging Animals Antineoplastic Agents Apoptosis Apoptotic Atherosclerosis Automobile Driving BAX gene BCL2 gene Bax protein Biological Models Birth Blood Vessels Blood capillaries Cancer Patient Cancer Survivor Cell Death Cell physiology Cells Cellular Morphology Cellular Stress Chemotherapy and/or radiation Cisplatin Clinic Clinical Complement Cytochrome P450 Cytotoxic agent DNA Databases Detection Development Disease model Doxorubicin Elderly Endothelial Cells Exposure to External Beam Radiation Therapy FDA approved Future Gene Expression Gene Family Gene Proteins Health Heart Heart failure Human Hypertension Impairment In Vitro International Ionizing radiation Irreversible Toxicity Ischemia Knockout Mice Knowledge Laboratories Lead Life Link Longevity Malignant Neoplasms Measurement Measures Migration Assay Mitochondria Molecular Morphology Mus Normal tissue morphology Outcome Patients Peripheral Pharmaceutical Preparations Play Predisposition Prevention Protein Family Quality of life Radiation therapy Regimen Regulation Role Signal Pathway Smooth Muscle Myocytes Testing Therapeutic Thrombosis Tissues Toxic effect Tube Tyrosine Kinase Inhibitor VDAC1 gene Vascular Diseases Vascular Endothelial Cell Vascular Endothelium Vascular Smooth Muscle Vegf Inhibitor Work cancer cell cancer therapy cell injury cell type chemotherapy cytotoxic differentiation protocol effective therapy endothelial stem cell experience experimental study high risk human model improved in vivo induced pluripotent stem cell innovation mimetics neonate neoplastic cell pharmacovigilance prevent pro-apoptotic protein response screening targeted agent therapy development transcriptomics tumor tumor xenograft vascular stress venous thromboembolism

项目摘要

PROJECT SUMMARY Cancer treatments have evolved extensively over the past few decades, leading to vast improvements in overall survival and cure rates. However, the collateral damage inflicted upon healthy tissues by both targeted and cytotoxic agents frequently causes life-threatening irreversible toxicities. Some of the most common toxicities include therapy-induced vascular impairments such as atherosclerosis, heart failure, ischemia, acute thrombosis, and venous thromboembolism. Despite their widespread use, it is poorly understood how chemotherapies and ionizing radiation cause vascular toxicities. Most cancer therapies typically induce apoptosis (programmed cell death) by damaging common cellular components such as DNA or by blocking critical signaling pathways. Since vascular cells are also exposed to these agents at high concentrations, they could be vulnerable to therapy-induced apoptosis. However, the vasculature is comprised of several cell types including vascular endothelial and smooth muscle cells; it is unknown which cells are sensitive to anti-cancer agents and how they may contribute to long-term vascular dysfunction in patients. Using human induced pluripotent stem cells (hiPSCs) for in vitro disease modeling, we will investigate vascular toxicities in hiPSC- derived vascular endothelial cells and vascular smooth muscle cells. Utilizing robust differentiation protocols already established in our laboratory, we will rigorously test how the survival and function of these cells are affected by cancer treatments. We will also characterize the regulation of apoptosis in both vascular cell types by measuring apoptotic priming and expression of BCL-2 family proteins. Additionally, we will look at the functional and morphological changes that these cells undergo in response to cancer treatments that may contribute to vascular toxicities. We hypothesize that each vascular cell type possesses differential levels of apoptotic priming, and unique vulnerabilities to our panel of FDA-approved cancer therapies that drive therapy- induced vascular toxicities. Our studies will elucidate potential mechanisms and determine contributions of each cell type to vascular toxicities observed in cancer patients. Further, since aging is known to play a role in both vascular toxicity and regulation of apoptosis, we will investigate how age affects apoptotic priming and therapy sensitivity of vascular cells. We will replicate key experiments in mice at various life stages (neonate, juvenile, adult and advanced age) to validate our in vitro findings and elucidate how age affects the development of vascular toxicities. We will also utilize endothelial cell-specific BAX/BAK double knockout mice to determine the extent to which apoptosis blockade can ameliorate vascular toxicity induced by cancer treatment. Altogether, our work will test how apoptosis regulation affects the sensitivity of vascular cells to chemotherapy and radiation and how this is altered by aging. These results will lay the groundwork for improved therapy regimens in the clinic that may decrease long-term vascular toxicities in cancer patients.

项目概要在过去的几十年里，癌症治疗取得了广泛的发展，导致了癌症治疗的巨大进步。总生存率和治愈率。然而，这两种目标对健康组织造成的附带损害细胞毒性剂经常引起危及生命的不可逆毒性。一些最常见的毒性包括治疗引起的血管损伤，如动脉粥样硬化、心力衰竭、缺血、急性血栓形成和静脉血栓栓塞。尽管它们被广泛使用，但人们对其如何使用却知之甚少。化疗和电离辐射会引起血管毒性。大多数癌症治疗通常会诱导通过破坏 DNA 等常见细胞成分或阻断细胞凋亡（程序性细胞死亡）关键信号通路。由于血管细胞也暴露于高浓度的这些试剂中，因此它们可能容易受到治疗诱导的细胞凋亡的影响。然而，脉管系统由多种细胞类型组成包括血管内皮细胞和平滑肌细胞；目前尚不清楚哪些细胞对抗癌敏感药物以及它们如何导致患者长期血管功能障碍。利用人体感应多能干细胞 (hiPSC) 用于体外疾病模型，我们将研究 hiPSC 中的血管毒性- 衍生血管内皮细胞和血管平滑肌细胞。利用强大的分化方案我们的实验室已经建立，我们将严格测试这些细胞的存活和功能如何受癌症治疗的影响。我们还将描述两种血管细胞类型中细胞凋亡的调节通过测量细胞凋亡引发和 BCL-2 家族蛋白的表达。此外，我们还将关注这些细胞响应癌症治疗而发生的功能和形态变化，可能导致血管毒性。我们假设每种血管细胞类型都具有不同水平的细胞凋亡启动，以及我们 FDA 批准的驱动治疗的癌症疗法组的独特弱点 - 诱发血管毒性。我们的研究将阐明潜在的机制并确定在癌症患者中观察到的每种细胞类型对血管的毒性。此外，由于已知衰老在血管毒性和细胞凋亡的调节，我们将研究年龄如何影响细胞凋亡启动和血管细胞的治疗敏感性。我们将在不同生命阶段（新生儿、青少年、成人和老年）来验证我们的体外研究结果并阐明年龄如何影响血管毒性的发展。我们还将利用内皮细胞特异性 BAX/BAK 双敲除小鼠确定细胞凋亡阻断可以在多大程度上改善癌症引起的血管毒性治疗。总而言之，我们的工作将测试细胞凋亡调节如何影响血管细胞的敏感性化疗和放疗以及衰老如何改变这一点。这些结果将为改进的临床治疗方案可能会减少癌症患者的长期血管毒性。