Pilot-Project 1

试点项目 1

• 批准号: 10762292
• 负责人: Deborah Lefkowitz
• 金额: $ 5.23万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10762292
• 关键词: ATAC-seq; Acetyl Coenzyme A; Acetylation; African American; African ancestry; Biological Markers; Black race; Blood; Blood Vessels; Breast Cancer survivor; California; Cardiovascular Diseases; Cell Aging; Cell Separation; Cells; ChIP-seq; Chemoprevention; Chromatin; City of Hope Comprehensive Cancer Center; Clinical Trials; Code; Collection; Comprehensive Cancer Center; Cytotoxic Chemotherapy; Data; Diabetic Nephropathy; Doctor of Medicine; Eating; Epigenetic Process; Estrogen receptor negative; Failure; Gene Abnormality; Genes; Genetic Transcription; Grant; Growth; Health; Heart; Histone Acetylation; Human Resources; Hyperinsulinism; IRF1 gene; Inflammation; Inflammatory; Institutional Review Boards; Insulin; Insulin Resistance; Interferon-beta; Interleukin-6; Joints; Kidney; Latina; Latina Population; Leukocytes; Link; Malignant Neoplasms; Mentors; Mentorship; Metabolic; Metformin; Mitochondria; Muscle Cells; NF-kappa B; Non-Insulin-Dependent Diabetes Mellitus; Not Hispanic or Latino; Organ; Patients; Phase; Phenotype; Pilot Projects; Premature aging syndrome; Production; Proteins; Regulation; Reproducibility; Research; Research Personnel; Respiration; Risk; Running; Serum; Supervision; Surveys; TNF gene; Testing; Therapeutic Trials; Time; Training; Transplantation; Universities; Woman; clinical biomarkers; cohort; community center; cytokine; drug development; drug repurposing; experience; fighting; follow-up; malignant breast neoplasm; medical schools; mouse model; outreach; pilot trial; recruit; senescence; standard of care; stem cells; transcriptomics

University of California, Riverside (UCR) has never implemented a therapeutic trial. Building therapeutic trial capacity at UCR was our biggest challenge – and the biggest failure - of our P20 planning grant. City of Hope Comprehensive Cancer Center (CoHCCC) runs hundreds of therapeutic trials (Phase 0 to 4) ranging from chemoprevention to Phase 1 CAR-Tcell therapy. In our P20 planning grant, we leveraged an on-going CoHCCC outreach trial testing, in women with insulin-resistance, testing the ability of metformin to reduce 1) production of inflammatory cytokines and 2) circulating senescent inflammatory cells. While CoHCCC has implemented this trial in community centers, the trial rapidly ran into problems at UCR. Key issues were 1) lack of experience of the UCR Institutional Review Board (IRB) and 2) a need for greater mentorship of UCR investigators. In this U54 grant, we are determined to help UCR open therapeutic trials; however, first we need to build capacity. U54 Pilot Project 1 uses state-of-the-art single cell-transcriptomics and -ATACseq in the context of a simple therapeutic trial. This trial tests the ability of standard-of-care metformin to reduce inflammation in insulin-resistant breast cancer survivors. Under the oversight of David Lo, M.D. Dean of Research at UCR Medical School, the trial will be conducted at CoH using CoH patients, personnel, and IRB. CoH will provide hands-on training in 1) therapeutic trials and 2) rigor and reproducibility of clinical biomarkers. CoH’s IRB will use this opportunity to mentor UCR’s IRB. In Year 3, the trial will be opened for accrual at UCR. Metformin is known to reverse insulin- resistance and remove senescent cells. In this capacity building trial – we aim to test in insulin-resistant Latina and African American/Black breast cancer survivors, the hypothesis that metformin can 1) restore metabolic health (reverse insulin-resistance), 2) reduce H3K9ac-chromatin opening of genes coding for IL6/TNFα/INFβ, and 3) reduce inflammation and circulating SASP cells. Aim 1 will build UCR clinical-trials capacity by conducting a UCR-CoH partnered trial at CoH in a diverse cohort. Aim 2 will provide capacity building in biospecimen collection, biomarker analysis, and rigor and reproducibility. In Aim 3 CoH IRB continues its mentorship (started during P20) of UCR IRB in regulations for therapeutic trials.

加州大学滨江分校（UCR）从未实施过治疗试验。建筑治疗试验 UCR的能力是我们P20规划补助金的最大挑战-也是最大的失败。City of Hope 综合癌症中心（CoHCCC）进行了数百项治疗试验（0期至4期）， 第一阶段CAR-T细胞治疗的化学预防。在我们的P20规划拨款中，我们利用了正在进行的CoHCCC 在胰岛素抵抗女性中进行的外展试验测试，测试二甲双胍减少1） 炎性细胞因子和2）循环衰老炎性细胞。虽然CoHCCC已经实施了这一点， 在社区中心的试验中，试验很快在UCR遇到了问题。关键问题是：（1）缺乏 UCR机构审查委员会（IRB）和2）需要更多的UCR研究人员的指导。在U 54 我们决心帮助UCR开展治疗试验;然而，首先我们需要建立能力。U 54飞行员 项目1使用最先进的单细胞转录组学和ATACseq在一个简单的治疗背景下， 审判该试验测试了标准治疗二甲双胍减少胰岛素抵抗乳腺癌患者炎症的能力。 癌症幸存者在医学博士大卫罗的监督下UCR医学院的研究主任，该试验将 由CoH患者、人员和IRB在CoH进行。CoH将提供以下方面的实践培训：1） 治疗试验和2）临床生物标志物的严格性和可重复性。CoH的IRB将利用这个机会 指导UCR的IRB在第3年，该试验将在UCR开放进行累积。二甲双胍可以逆转胰岛素- 抵抗和去除衰老细胞。在这项能力建设试验中，我们的目标是在胰岛素抵抗的拉丁美洲人中进行测试。 和非裔美国人/黑人乳腺癌幸存者，二甲双胍可以1）恢复代谢的假设， 健康（逆转胰岛素抵抗），2）减少编码以下基因H3 K9 ac-染色质开放 IL 6/TNFα/INFβ，和3）减少炎症和循环SASP细胞。目标1将建立UCR临床试验 通过在CoH在不同队列中进行UCR-CoH合作试验来提高能力。目标2将提供能力建设 在生物样本收集、生物标记物分析以及严谨性和再现性方面。在目标3中，CoH IRB继续其 指导（在P20期间开始）UCR IRB的治疗试验法规。