CYP1 Inhibition as a New Therapeutic Strategy for Doxorubicin Cardiomyopathy

CYP1 抑制作为阿霉素心肌病的新治疗策略

• 批准号: 10549294
• 负责人: Aarti Asnani
• 金额: $ 16.74万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10549294
• 关键词: Advisory Committees; Animal Model; Anthracycline; Arachidonic Acids; Area; Biochemical Pathway; Biology; Breast Lymphoma; CYP1A2 gene; Cancer Survivor; Cardiac; Cardiometabolic Disease; Cardiomyopathies; Cardiotoxicity; Cardiovascular system; Cellular biology; Chemicals; Chemistry; Clinical; Collaborations; Complement; Congestive Heart Failure; Core Facility; Cytochrome P450; Cytochrome a; Data; Development; Development Plans; Dexrazoxane; Disease model; Doxorubicin; Echocardiography; Environment; Enzymes; Equipment; Estrogens; FDA approved; Faculty; Family; Fishes; Foundations; Funding; Furanocoumarins; Future; Genetic; Genetic Models; Goals; Heart; Heart Injuries; Human; Institution; Investigation; Israel; Knock-out; Knockout Mice; Laboratories; Lipids; Literature; Liver; Lymphoma; Malignant Neoplasms; Mediating; Medical; Medical center; Medicine; Mentors; Mentorship; Metabolism; Modeling; Morbidity - disease rate; Mus; Mutagenesis; Oncologist; Oncology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Plasma; Population; Positioning Attribute; Postdoctoral Fellow; Protein Isoforms; Proteomics; Recording of previous events; Reporting; Research; Rodent; Role; Scientist; Second Primary Cancers; Series; Site; Techniques; Therapeutic; Therapeutic Uses; Tissues; Toxic Environmental Substances; Toxic effect; Training; Transgenic Organisms; Tumor Tissue; Universities; Utah; Work; Xenograft Model; Zebrafish; analog; antitumor effect; cancer cell; cancer therapy; cancer type; cardioprotection; career development; chemotherapy; drug discovery; efficacy testing; experimental study; heart function; heart preservation; inhibitor; instructor; knock-down; leukemia; malignant breast neoplasm; medical schools; mortality; mouse model; new therapeutic target; novel therapeutic intervention; novel therapeutics; oncology program; overexpression; prevent; recruit; response; skills; small molecule; translational study; tumor; tumorigenesis

PROJECT SUMMARY This proposal reflects a five-year career development plan for Dr. Aarti Asnani, a staff cardiologist at Beth Israel Deaconess Medical Center (BIDMC) and an Instructor at Harvard Medical School (HMS). Dr. Asnani’s research focuses on anthracycline-induced cardiomyopathy, a major contributor to morbidity and mortality in the growing population of cancer survivors. Based on her chemistry background and clinical expertise in cardio-oncology, Dr. Asnani is uniquely well-positioned to characterize the biochemical pathways that contribute to chemotherapy-induced cardiotoxicity in order to identify new cardioprotective therapies. In 2017, Dr. Asnani was recruited to BIDMC where she serves as Associate Director of the Cardio-Oncology Program. Dr. Robert Gerszten, Chief of Cardiovascular Medicine at BIDMC, has been very involved in Dr. Asnani’s career development since 2006 and will serve as the primary on-site mentor for this project. Dr. Gerszten has expertise in the use of metabolite profiling and proteomics to identify new pathways that contribute to cardiometabolic disease. Dr. Asnani will also continue to receive mentorship from her postdoctoral advisor, Dr. Peterson, whose laboratory moved to the University of Utah in January 2017. Dr. Peterson is an expert in chemical biology and has pioneered the use of zebrafish for drug discovery and mutagenesis. Both preceptors are well-funded and have a longstanding history of mentoring successful junior faculty. In addition to this combined training approach, Dr. Asnani’s Scientific Advisory Committee consists of world-class scientists (Drs. MacRae, Liao, Pandolfi, and Nebert) who will contribute expertise in animal models of cardiomyopathy, cancer cell biology, and pharmacology. Dr. Asnani benefits from strong institutional support and a rich research environment. She has access to a broad range of core facilities and equipment, scientific expertise, and opportunities for collaboration that extend across BIDMC, Longwood Medical Area, and HMS. In this application, Dr. Asnani has outlined a series of experiments to elucidate the role of Cytochrome P450 family 1 (CYP1) enzymes as new therapeutic targets for doxorubicin cardiotoxicity. Prior work in Dr. Peterson’s lab identified the small molecule visnagin, a CYP1 inhibitor, as protecting against doxorubicin-induced cardiomyopathy in zebrafish and mice. In this proposal, Dr. Asnani will use transgenic zebrafish models to identify the specific CYP1 isoform responsible for cardiotoxicity. She will use Cyp1a1/1a2/1b1(−/−) knockout mice to establish whether genetic inhibition of CYP1 enzymes protects against doxorubicin cardiotoxicity in a mammalian model. Finally, she will use a mouse xenograft model to determine the effect of CYP1 inhibition on doxorubicin’s anti-tumor activity. By completing the proposed project, Dr. Asnani will complement her prior training in metabolite profiling, chemical biology, and zebrafish models with additional training in transgenic techniques and mouse models. These experiments will form the basis for an independent investigative platform that will seek to develop new treatments for patients with chemotherapy-induced cardiotoxicity.

项目总结

项目成果

Circulating hemopexin modulates anthracycline cardiac toxicity in patients and in mice.

循环血兴蛋白调节患者和小鼠的蒽环类心脏毒性。

• DOI: 10.1126/sciadv.adc9245
• 发表时间: 2022-12-23
• 期刊: Science advances
• 影响因子: 13.6

Zebrafish Models of Cancer Therapy-Induced Cardiovascular Toxicity.

• DOI: 10.3390/jcdd8020008
• 发表时间: 2021-01-22
• 期刊: Journal of cardiovascular development and disease
• 影响因子: 2.4
• 作者: Lane S;More LA;Asnani A
• 通讯作者: Asnani A

Cyp1 Inhibition Prevents Doxorubicin-Induced Cardiomyopathy in a Zebrafish Heart-Failure Model.

• DOI: 10.1002/cbic.201900741
• 发表时间: 2020-07-01
• 期刊: Chembiochem : a European journal of chemical biology
• 作者: Lam PY;Kutchukian P;Anand R;Imbriglio J;Andrews C;Padilla H;Vohra A;Lane S;Parker DL Jr;Cornella Taracido I;Johns DG;Beerens M;MacRae CA;Caldwell JP;Sorota S;Asnani A;Peterson RT
• 通讯作者: Peterson RT