Omics of Pain in the Context of Declining Estrogen

雌激素下降背景下的疼痛组学

• 批准号: 10701075
• 负责人: Monica Ann Wagner
• 金额: $ 24.46万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701075
• 关键词: Address; Adherence; Adrenergic Agents; Architecture; Aromatase Inhibition; Aromatase Inhibitors; Bioinformatics; Biological; Blood specimen; Brain; Breast; Breast Cancer Prevention Trial; Brief Pain Inventory; Cancer Center; Clinical; Colon; Competence; DNA; DNA Methylation; Data; Development; Ensure; Environment; Enzyme Inhibition; Estrogen decline; Estrogens; Faculty; Gene Expression; Gene Expression Regulation; Genes; Individual; Investigation; Knowledge; Lung; Malignant Neoplasms; Measures; Mediating; Medical center; Mentors; Modality; Molecular; Musculoskeletal Development; Musculoskeletal Pain; NCI-Designated Cancer Center; Newly Diagnosed; Pain; Pain Disorder; Pain interference; Pathway interactions; Phase; Phenotype; Positioning Attribute; Postmenopause; Prevention strategy; Production; Prostate; RNA; Recurrent Malignant Neoplasm; Research; Resources; Risk; Role; Sampling; Severities; Site; Symptoms; Testing; Therapeutic Intervention; Time; Training; Universities; Woman; alpha 2 agonist; antagonist; cancer pain; cancer recurrence; cancer therapy; cancer type; career development; chronic musculoskeletal pain; chronic pain; effective therapy; epigenomics; evidence base; experience; functional status; gray matter; health care service utilization; hormone receptor-positive; inhibitor therapy; innovation; interest; malignant breast neoplasm; methylome; neuroimaging; novel; pain inhibition; prevent; programs; recruit; response; sex; skills; therapy design; transcriptome; transcriptomics; treatment strategy; white matter; whole genome; Address; Adherence; Adrenergic Agents; Architecture; Aromatase Inhibition; Aromatase Inhibitors; Bioinformatics; Biological; Blood specimen; Brain; Breast; Breast Cancer Prevention Trial; Brief Pain Inventory; Cancer Center; Clinical; Colon; Competence; DNA; DNA Methylation; Data; Development; Ensure; Environment; Enzyme Inhibition; Estrogen decline; Estrogens; Faculty; Gene Expression; Gene Expression Regulation; Genes; Individual; Investigation; Knowledge; Lung; Malignant Neoplasms; Measures; Mediating; Medical center; Mentors; Modality; Molecular; Musculoskeletal Development; Musculoskeletal Pain; NCI-Designated Cancer Center; Newly Diagnosed; Pain; Pain Disorder; Pain interference; Pathway interactions; Phase; Phenotype; Positioning Attribute; Postmenopause; Prevention strategy; Production; Prostate; RNA; Recurrent Malignant Neoplasm; Research; Resources; Risk; Role; Sampling; Severities; Site; Symptoms; Testing; Therapeutic Intervention; Time; Training; Universities; Woman; alpha 2 agonist; antagonist; cancer pain; cancer recurrence; cancer therapy; cancer type; career development; chronic musculoskeletal pain; chronic pain; effective therapy; epigenomics; evidence base; experience; functional status; gray matter; health care service utilization; hormone receptor-positive; inhibitor therapy; innovation; interest; malignant breast neoplasm; methylome; neuroimaging; novel; pain inhibition; prevent; programs; recruit; response; sex; skills; therapy design; transcriptome; transcriptomics; treatment strategy; white matter; whole genome

PROJECT SUMMARY/ABSTRACT Chronic musculoskeletal pain (MSKP) is a significant problem in many women with hormone receptor- positive early stage breast cancer receiving treatment designed to prevent cancer recurrence by blocking estrogen production via systemic inhibition of the aromatase enzyme. MSKP interferes with functional status, adherence to therapy, and increases utilization of health care resources. Unfortunately, very little is known about the molecular mechanisms underlying MSKP related to a decline in estrogen in women with breast cancer. Evidence supports that dysregulation of adrenergic function is present in women with MSKP. In fact, both β-antagonists and α2-agonists have been investigated as treatment for MSKP pain disorders, and evidence from our group as well as others support a role for pain inhibition via α1-antagonists. The purpose of this K99R00 proposal is to provide the applicant with the necessary training and research experience to examine the dynamic RNA transcriptome and DNA methylome to identify genes and biological pathways that are involved in development of cancer pain. The purpose of the proposed K99 study is to generate knowledge about MSKP development within the context of declining estrogen in women with breast cancer. The K99 phase of this project capitalizes on data and blood samples generated through an ongoing project that recruits postmenopausal women newly diagnosed with early stage breast cancer who will receive aromatase inhibitor therapy (R01CA196762, the EPICC study). The K99 also benefits from an ongoing project generating DNA methylation data from blood samples of the women in the EPICC study (R01CA221882). The specific research aims for the K99 study are to (1) test the hypothesis that 6 months of decreased estrogen leads to changes in gene expression and this is related to changes in the pain phenotype in women with breast cancer; and (2) test the hypothesis that 6 months of decreased estrogen leads to changes in DNA methylation and this is related to changes in the pain phenotype in women with breast cancer. The K99 training plan leverages the superb research-intensive environment and resources at the University of Pittsburgh to ensure the applicant’s development of (a) proficiency in omics (particularly transcriptomics and epigenomics), (b) competency in analysis and bioinformatics of omics data, (c) proficiency in pain mechanisms, and (d) knowledge and skills for professional career development. The specific aims of the R00 study are to (1) identify changes in the regulation of genes that are associated with variability in cancer pain based on cancer type; (2) identify changes in the regulation of genes that are associated with variability in cancer pain based on cancer therapy; and (3) explore the potential mediating and moderating effects of sex on the relationship between gene regulation and pain. This research generates the knowledge needed to develop a research program focusing on developing a profile for predicting individuals at risk for chronic pain development that includes demographic, clinical, and omics data.

项目摘要/摘要 慢性肌肉骨骼疼痛（MSKP）是许多雌雄同体受体的女性的重要问题 阳性早期乳腺癌接受旨在通过阻塞来预防癌症复发的治疗 通过全身抑制芳香酶产生雌激素。 MSKP干扰功能状态， 遵守治疗，并增加对医疗资源的利用。不幸的是，很少知道 关于MSKP的分子机制与乳房女性的雌激素下降有关 癌症。有证据表明，MSKP女性呈现肾上腺功能的失调。实际上， 已经研究了β-抗抗氮学家和α2激动剂作为MSKP疼痛障碍的治疗方法，并且 我们小组以及其他人的证据支持通过α1-抗贡贡者抑制疼痛的作用。目的 该K99R00建议是为申请人提供必要的培训和研究经验 检查动态RNA转录组和DNA甲基甲基体，以鉴定基因和生物学途径 参与癌症疼痛的发展。拟议的K99研究的目的是产生知识 关于MSKP在乳腺癌女性雌激素下降的背景下的发展。 K99 该项目的阶段利用了通过正在进行的项目生成的数据和血液样本 绝经后妇女新诊断为早期乳腺癌，她们将接受芳香酶抑制剂 治疗（R01CA196762，EPICC研究）。 K99还受益于正在进行的生成DNA的项目 EPICC研究中女性血液样本的甲基化数据（R01CA221882）。具体研究 K99研究的目的是（1）检验以下假设：雌激素减少6个月会导致变化 基因表达，这与乳腺癌女性疼痛表型的变化有关。 （2）测试 雌激素减少6个月会导致DNA甲基化的变化，这与 乳腺癌女性疼痛表型的变化。 K99培训计划利用了极好的 匹兹堡大学的研究密集型环境和资源，以确保申请人的 （a）熟练程度的熟练程度（尤其是转录组学和表观基因组学），（b） OMICS数据的分析和生物信息学，（c）疼痛机制的熟练程度以及（d）知识和技能 职业发展。 R00研究的具体目的是（1）确定变化 调节基于癌症类型的癌症疼痛变异性相关的基因； （2）识别 基于癌症治疗的癌症疼痛变异性相关的基因调节的变化； （3）探索性别对基因关系的潜在介导和调节作用 调节和痛苦。这项研究产生了开发研究计划所需的知识 为了预测有慢性疼痛发育风险的个人的个人资料，包括 人口统计，临床和法律数据。