Cell free RNA liquid biopsies

无细胞 RNA 液体活检

• 批准号: 10363505
• 负责人: Roman Reggiardo
• 金额: $ 4.47万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10363505
• 关键词: Awareness; Biological; Biological Assay; Biology; Blood; Blood Cells; Blood specimen; Bone Marrow; Bone Marrow Aspiration; Bone marrow biopsy; COVID-19 patient; Cell Count; Cells; Classification; Clinical; Code; DNA Transposable Elements; Data; Data Set; Detection; Developmental Cell Biology; Diagnosis; Diagnostic; Diagnostic Procedure; Disease; Disease Marker; Doctor of Philosophy; Ensure; Environment; Event; Fibrosis; Generations; Genetic Transcription; Genomics; Genotype-Tissue Expression Project; Global Change; Goals; Growth; Health; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hemorrhage; Human; In Vitro; Individual; Infection; Label; Lead; Lung Adenocarcinoma; Mentorship; Mesenchymal Stem Cells; Methylation; Monitor; National Institute of Diabetes and Digestive and Kidney Diseases; PET/CT scan; Pathology; Patients; Performance; Plasma; Population; Production; RNA; RNA analysis; RNA marker; Recovery; Research; Research Personnel; Sampling; Sedation procedure; Techniques; Testing; The Cancer Genome Atlas; Tissue Sample; Tissues; Training; Transcriptional Regulation; Untranslated RNA; Validation; Whole Blood; X-Ray Computed Tomography; base; bone marrow mesenchymal stem cell; cell free DNA; cell type; cohort; cost; diagnostic biomarker; extracellular; extracellular vesicles; leukemia/lymphoma; liquid biopsy; machine learning algorithm; member; pain relief; pancreatic cancer patients; peripheral blood; progenitor; programs; side effect; single-cell RNA sequencing; specific biomarkers; stem cell biology; stem cell population; success; tool; transcriptome sequencing; tumorigenesis

ABSTRACT The ultimate goal of this proposal is to verify an RNA liquid biopsy platform and transition it to have specific utility for the study, and non-invasive assessment, of the hematopoietic bone marrow (BM) niche. In addition to their reliance of material excreted from dying, diseased cells, cell-free DNA (cfDNA) platforms are limited to primarily detecting changes in somatic genomic sequence, copy number, or methylation status. Many biological and clinical events, such as hematopoiesis, fibrosis, and tumorigenesis, are executed via global changes in transcriptional regulation. My PhD advisor Dr. Daniel Kim and I have established a platform for exRNA liquid biopsy in human blood-plasma that has demonstrated significant diagnostic and monitoring potential in both Pancreatic cancer and COVID-19 patients. I propose to continue this research to complete my PhD by assessing diagnostic performance of the exRNA platform in a new cohort of 60 lung adenocarcinoma (LUAD) patients with matched controls. Furthermore, I will apply my expertise in exRNA liquid biopsies to assay the transcriptional dynamics of hematopoiesis and hematopoietic stem cells (HSCs) in the bone marrow (BM) niche. Currently, bone marrow biopsies or aspirations are used to determine bone marrow health and production. These techniques are costly and require sedation and/or pain relief for the subject and have the potential to lead to long term discomfort, infection, excessive bleeding, and other side-effects. BM aspirations remain a critical diagnostic and monitoring tool for HSC transplant recovery, leukemias and lymphomas, blood cell pathologies, and infections of unknown origin but the primary readout remains identification and counting of cell types. I hypothesize that hematopoietic lineages within the BM secrete exRNA that reflect cell state and identity that can be used in a non-invasive RNA liquid biopsy for detailed study of transcription and populations within the BM. I propose to identify exRNA expressed and secreted by HSCs and the remaining hematopoietic lineage in order to develop a platform to deconvolute peripheral blood into constituent hematopoietic cell types without the need for HSC mobilization.

抽象的 该提案的最终目标是验证 RNA 液体活检平台并将其转变为具有特定用途 用于造血骨髓 (BM) 生态位的研究和非侵入性评估。除了他们的 依赖从死亡、患病细胞、游离 DNA (cfDNA) 平台排出的物质主要限于 检测体细胞基因组序列、拷贝数或甲基化状态的变化。许多生物和 临床事件，例如造血、纤维化和肿瘤发生，是通过全局变化来执行的 转录调控。我和我的博士生导师 Daniel Kim 博士建立了一个 exRNA 液体平台 人类血浆活检已显示出显着的诊断和监测潜力 胰腺癌和 COVID-19 患者。我建议继续这项研究以完成我的博士学位 评估 exRNA 平台在 60 例肺腺癌新队列中的诊断性能 （LUAD）患者与匹配的对照。此外，我将运用我在 exRNA 液体活检方面的专业知识 测定骨髓中造血和造血干细胞 (HSC) 的转录动态 （BM）利基。目前，骨髓活检或穿刺用于确定骨髓健康状况和 生产。这些技术成本高昂并且需要对受试者进行镇静和/或缓解疼痛，并且具有 可能导致长期不适、感染、出血过多和其他副作用。 BM的愿望 仍然是 HSC 移植恢复、白血病和淋巴瘤、血液的重要诊断和监测工具 细胞病理学和未知来源的感染，但主要读数仍然是识别和计数 细胞类型。我假设 BM 内的造血谱系分泌反映细胞状态的 exRNA 可用于非侵入性 RNA 液体活检以详细研究转录和群体的身份 BM 内。我建议鉴定 HSC 表达和分泌的 exRNA 以及其余的 造血谱系，以开发一个将外周血解卷积为成分的平台 无需 HSC 动员的造血细胞类型。