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

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

展开

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.

项目摘要在过去的几十年中总体生存率和治愈率。但是，两者都针对健康组织造成的附带损害细胞毒性剂经常引起威胁生命的不可逆毒性。一些最常见的毒性包括治疗引起的血管障碍，例如动脉粥样硬化，心力衰竭，缺血，急性血栓形成和静脉血栓栓塞。尽管它们广泛使用，但众所周知化学疗法和电离辐射引起血管毒性。大多数癌症疗法通常诱导凋亡（程序性细胞死亡）通过损害常见的细胞成分（例如DNA）或阻塞临界信号通路。由于血管细胞也以高浓度暴露于这些药物，因此可能容易受到治疗引起的凋亡。但是，脉管系统由几种细胞类型组成包括血管内皮和平滑肌细胞；尚不清楚哪些细胞对抗癌者敏感药物及其如何导致患者长期血管功能障碍。使用人类诱导多能干细胞（HIPSC）用于体外疾病建模，我们将研究HIPSC-的血管毒性衍生的血管内皮细胞和血管平滑肌细胞。利用强大的分化协议我们将在我们的实验室中建立，我们将严格测试这些细胞的生存和功能如何受癌症治疗的影响。我们还将表征两种血管细胞类型中凋亡的调节通过测量Bcl-2家族蛋白的凋亡启动和表达。此外，我们将查看这些细胞对癌症治疗发生的功能和形态变化可能会发生有助于血管毒性。我们假设每种血管细胞类型都具有差异水平凋亡的启动以及我们对FDA批准的癌症疗法小组的独特脆弱性，这些疗法可以推动治疗 - 诱导血管毒性。我们的研究将阐明潜在机制并确定在癌症患者中观察到的每种细胞类型对血管毒性。此外，由于已知衰老会在血管毒性和凋亡的调节，我们将研究年龄如何影响凋亡启动和血管细胞的治疗敏感性。我们将在各个生命阶段复制小鼠的关键实验（新生儿，少年，成人和高龄），以验证我们的体外发现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的Bax/Bak双基因敲除小鼠为了确定凋亡封锁可以减轻癌症诱导的血管毒性的程度治疗。总之，我们的工作将测试凋亡调节如何影响血管细胞对化学疗法和放射线以及衰老如何改变。这些结果将为改善诊所的治疗方案可能会降低癌症患者的长期血管毒性。