Macrophage-targeted lncRNA-regulating nanoparticles for glioblastoma treatment

巨噬细胞靶向 lncRNA 调节纳米颗粒用于胶质母细胞瘤治疗

• 批准号: 10701432
• 负责人: Edjah Nduom
• 金额: $ 39.13万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701432
• 关键词: Acceleration; Affect; Brain Neoplasms; CD14 gene; Cancer Patient; Cell physiology; Cells; Clinical Trials; Data; Development; Disease Progression; Flow Cytometry; Future; Genetic Materials; Genetic Transcription; Genetic study; Genetically Engineered Mouse; Glioblastoma; Goals; Immune; Immune response; Immune system; Immunologic Stimulation; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Infiltration; Interleukin-13; Interleukin-4; Intracranial Neoplasms; Knowledge; Literature; Macrophage; Magnetic Resonance Imaging; Malignant neoplasm of brain; Mediating; Modeling; Mus; Myeloid Cells; Operative Surgical Procedures; Outcome; Patient-Focused Outcomes; Patients; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Population; Radiation; Research; Resistance; Science; Small Interfering RNA; Sorting; Suspensions; Therapeutic; Tissues; Treatment Efficacy; Tumor Promotion; Tumor-associated macrophages; Untranslated RNA; Work; base; bioinformatics tool; cancer therapy; candidate identification; cell type; chemotherapy; clinical development; differential expression; immunoregulation; improved; improved outcome; innovation; monocyte; mouse model; nanoparticle; nanoparticle delivery; neoplastic cell; novel; novel therapeutics; overexpression; peripheral blood; pre-clinical; response; standard care; theranostics; therapeutic target; transcriptome sequencing; treatment strategy; tumor; tumor progression; tumor-immune system interactions

There is a critical need to identify mechanisms whereby abnormally regulated lncRNAs in macrophages drive progression of GBM and ways to target these lncRNAs preclinically. Our long-term goal is to accelerate the development of immune therapeutics targeting dysregulated lncRNAs to improve outcomes of GBM patients. Our overall objective for this application is to establish a delivery platform targeting novel GBM-specific lncRNAs that promote tumor progression. Our central hypothesis is that overexpression of lncRNAs in TAMs promote GBM tumor progression and immune suppression and are targetable with nanoparticles. The rationale for the proposed research is that evidence of nanoparticle-based targeting of dysregulated GBM-specific lncRNAs will provide new opportunities for the continued development of novel treatment strategies focused on inhibiting TAM-mediated immune suppression. Aim 1: Identify candidate lncRNAs mediating GBM progression. Our approach will be to perform deep bulk RNASeq of CD14+ cell subsets sorted from single cell suspensions of fresh GBM tissue and compare these to the peripheral blood of GBM patients and normal controls to identify differentially expressed lncRNAs, then use bioinformatic tools to choose lncRNAs that are likely to contribute to GBM immune suppression. Our working hypothesis is that TAMs overexpress lncRNAs associated with promotion of immune suppression in GBM beyond those identified from PBMCs alone. Aim 2. Determine the effect(s) of candidate lncRNA depletion on TAM phenotype and function. Our approach will be to deplete candidate lncRNAs in monocytes using siRNA. We will functionally characterize the response to depletion of these lncRNAs and begin mechanistic characterization of novel lncRNAs from Aim 1. Our working hypothesis is that depleting target lncRNAs will change the phenotype and function of these cells, making them resistant to M2-like polarization by IL-4 and IL-13, maintaining a more immune-stimulating state. Aim 3. Develop lncRNA targeted theranostic nanoparticles for lncRNA depletion in TAMs. Our approach will be to further develop MRI trackable nanoparticles for depletion of our preliminary target lncRNAs and any lncRNAs identified in Aim 1 in our genetically engineered murine model of GBM. Our working hypothesis is that our nanoparticles will deplete M2-like TAMs in the murine tumors and improve survival in this model. Our contribution here is expected to be the identification of novel lncRNAs with functional relevance in GBM TAMs and a translational platform for their delivery in murine models of GBM. These contributions will be significant because they are expected to represent an important next step toward future development and clinical trials of novel immune therapeutics for patients with this devastating brain cancer. The proposed research is innovative, in our opinion, because it represents a substantive departure from the status quo by focusing on discovery of immune-related lncRNAs that have been identified from GBM patient myeloid cells and by using nanoparticles to modulate the immune system by targeting these lncRNAs.

目前迫切需要确定巨噬细胞中异常调节的lncRNA驱动巨噬细胞凋亡的机制。 GBM的进展和临床前靶向这些lncRNA的方法。我们的长期目标是加快 开发靶向失调的lncRNA的免疫治疗剂以改善GBM患者的结果。 我们对该应用的总体目标是建立一个针对新型GBM特异性的递送平台。 lncRNA促进肿瘤进展。我们的中心假设是TAM中lncRNA的过度表达 促进GBM肿瘤进展和免疫抑制，并且可以用纳米颗粒靶向。的理由 对于拟议的研究是，基于纳米颗粒的GBM特异性靶向失调的证据， lncRNA将为持续开发新的治疗策略提供新的机会， 抑制TAM介导的免疫抑制。目的1：鉴定介导GBM的候选lncRNA 进展我们的方法将是对从单克隆抗体中分选的CD 14+细胞亚群进行深度批量RNASeq。 新鲜GBM组织的细胞悬液，并将其与GBM患者和正常人的外周血进行比较 对照以识别差异表达的lncRNA，然后使用生物信息学工具选择 可能会导致GBM免疫抑制。我们的假设是TAM过度表达lncRNA 与GBM中免疫抑制的促进相关，超出了仅从PBMC中鉴定的那些。目标2. 确定候选lncRNA缺失对TAM表型和功能的影响。我们的方法 将是使用siRNA去除单核细胞中的候选lncRNA。我们将从功能上描述响应 耗尽这些lncRNA，并开始对来自Aim 1的新型lncRNA进行机械表征。我们 工作假设是耗尽靶lncRNA将改变这些细胞的表型和功能， 使它们抵抗IL-4和IL-13引起的M2样极化，保持更强的免疫刺激状态。 目标3.开发lncRNA靶向治疗诊断纳米颗粒，用于TAM中的lncRNA消除。我们的方法 将进一步开发MRI可跟踪的纳米颗粒，用于消除我们的初步目标lncRNA和任何 在我们的GBM的基因工程鼠模型中的Aim 1中鉴定的lncRNA。我们的假设是 我们的纳米颗粒将耗尽小鼠肿瘤中的M2样TAM，并提高该模型的存活率。我们 本文的贡献预计是鉴定在GBM TAM中具有功能相关性的新型lncRNA 和用于在GBM的鼠模型中递送它们的翻译平台。这些贡献将是巨大的 因为它们有望代表未来开发和临床试验的重要下一步， 新的免疫疗法来治疗这种毁灭性的脑癌患者。拟议的研究是 我们认为，这是一项创新，因为它实质性地改变了现状， 从GBM患者骨髓细胞中鉴定的免疫相关lncRNA的发现， 通过靶向这些lncRNA来调节免疫系统。