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.

加州大学河滨分校(UCR)从未实施过治疗试验。构建治疗性试验 UCR的运力是我们P20规划拨款的最大挑战--也是最大的失败。希望之城 综合癌症中心(CoHCCC)运行数百项治疗试验(0至4期)，范围从 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 外展试验测试，在患有胰岛素抵抗的妇女中，测试二甲双胍减少1) 炎性细胞因子和2)循环衰老性炎症细胞。虽然CoHCCC已经实施了这一点 在社区中心进行试验后，UCR的试验很快就遇到了问题。关键问题是1)缺乏经验 UCR机构审查委员会(IRB)和2)需要对UCR调查人员进行更多的指导。在这辆U54上 格兰特，我们决心帮助UCR开启治疗试验；然而，首先我们需要建设能力。U54飞行员 项目1使用最先进的单细胞转录和ATACseq在简单的治疗性 审判。这项试验测试了标准护理二甲双胍减轻胰岛素抵抗乳房炎症的能力。 癌症幸存者。在UCR医学院医学博士院长David Lo的监督下，这项试验将 在COH使用COH患者、人员和IRB进行。COH将在1)中提供实践培训 治疗试验和2)临床生物标记物的严密性和重复性。CoH的IRB将利用这个机会 Mentor UCR的IRB。在第三年，该试用将在UCR开始计分。已知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，我们的目标是测试抵抗胰岛素的拉丁语 和非裔美国人/黑人乳腺癌幸存者，二甲双胍可以恢复新陈代谢的假设 健康(逆转胰岛素抵抗)，2)减少H3K9ac-染色质开放的编码基因 IL 6/肿瘤坏死因子α/干扰素β，以及3)减少炎症和循环中的SASP细胞。AIM 1将建立UCR临床试验 通过在COH在不同的队列中进行UCR-COH合作试验来提高能力。AIM 2将提供能力建设 在生物标本收集、生物标志物分析以及严密性和重复性方面。在Aim 3 Coh IRB继续它的 UCR IRB在治疗试验规则中的指导(从P20开始)。