Pilot Project 1

试点项目1

基本信息

批准号：
10762162
负责人：
VICTORIA L. SEEWALDT
金额：
$ 11.69万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-22 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10762162
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

项目摘要

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。建造治疗试验 UCR的能力是我们P20计划赠款中我们最大的挑战，也是最大的失败。希望之城综合癌症中心（COHCCC）进行数百次治疗试验（0到4阶段）对第1阶段的Car-Tcell治疗的化学预防。在我们的P20计划赠款中，我们利用了正在进行的COHCCC 在具有胰岛素抵抗的女性中进行外联试验测试，测试二甲双胍降低的能力1）炎性细胞因子和2）循环的感觉炎症细胞。虽然CoHCCC已实施此功能在社区中心的审判中，该试验迅速遇到了UCR问题。关键问题是1）缺乏 UCR机构审查委员会（IRB）和2）需要对UCR调查人员进行更大的心态。在这个U54中格兰特，我们决心帮助UCR开放式治疗试验；但是，首先我们需要建立能力。 U54飞行员项目1在简单疗法的背景下使用最先进的单细胞转录组和-atacseq 审判。该试验测试了护理标准二甲双胍降低胰岛素乳房感染的能力癌症存活。在UCR医学院研究的医学博士院长David Lo的监督下，审判将使用COH患者，人员和IRB在COH上进行。 COH将在1中提供动手培训治疗试验和2）临床生物标志物的严格性和可重复性。 COH的IRB将利用这个机会导师UCR的IRB。在第三年，该试验将在UCR开放。已知二甲双胍可以逆转胰岛素电阻并去除感觉细胞。在这个能力建筑试验中 - 我们旨在测试耐胰岛素的拉丁裔和非裔美国人/黑色乳腺癌的存活，二甲双胍可以1）恢复代谢的假设健康（反向胰岛素抵抗），2）减少编码基因的H3K9AC-染色质开放 IL6/TNFα/INFβ，3）减少炎症和循环SASP细胞。 AIM 1将建立UCR临床试验通过在潜水员队列的COH进行UCR-COH合作试验来实现容量。 AIM 2将提供能力建设在AIM 3 COH IRB中继续在治疗试验的法规中，属于UCR IRB的脑膜（在P20期间开始）。