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.

迫切需要确定巨噬细胞中异常调节的LNCRNA的机制 GBM的进展以及临床上针对这些LNCRNA的方法。我们的长期目标是加速 靶向失调的LNCRNA的免疫疗法的开发以改善GBM患者的预后。 我们对该应用程序的总体目标是建立一个针对新型GBM特异性的交付平台 促进肿瘤进展的LNCRNA。我们的中心假设是TAM中LNCRNA的过表达 促进GBM肿瘤进展和免疫抑制，并用纳米颗粒靶向。理由 对于拟议的研究，是基于纳米颗粒的靶向不体GBM特异性的靶向的证据 lncrnas将为持续发展的新型治疗策略提供新的机会 抑制TAM介导的免疫抑制。目标1：确定介导GBM的候选lncRNA 进展。我们的方法是执行从单个的CD14+细胞子集的深层RNASEQ 新鲜GBM组织的细胞悬浮液，并将其与GBM患者的外周血进行比较 识别差异表达的lncRNA的控件，然后使用生物信息学工具选择LNCRNA 可能有助于GBM免疫抑制。我们的工作假设是TAM过表达LNCRNA 与仅在PBMC中发现的GBM中促进免疫抑制的促进有关。目标2。 确定候选LNCRNA耗竭对TAM表型和功能的影响。我们的方法 将使用siRNA在单核细胞中耗尽候选LNCRNA。我们将在功能上表征响应 耗尽这些LNCRNA，并开始从AIM 1中对新型LNCRNA的机械表征。 工作假设是耗尽靶标LNCRNA将改变这些细胞的表型和功能， 通过IL-4和IL-13对它们抗M2样偏振具有抵抗力，保持了更为免疫刺激的状态。 AIM 3。开发靶向的pargion固醇纳米颗粒以在TAM中进行lncRNA耗竭。我们的方法 将进一步开发可跟踪的纳米颗粒，以耗尽我们的初步靶标和任何 LNCRNA在我们的GBM的基因工程鼠模型中在AIM 1中鉴定出来。我们工作的假设是 我们的纳米颗粒会在鼠肿瘤中耗尽M2样TAM，并在该模型中提高生存率。我们的 预计此处的贡献将是对GBM TAM具有功能相关性的新型LNCRNA的识别 以及它们在GBM鼠模型中交付的转化平台。这些贡献将是重要的 因为期望它们代表着未来发展和临床试验的重要下一步 这种毁灭性脑癌患者的新型免疫疗法。拟议的研究是 在我们看来，创新性，因为它通过专注于现状代表了与现状的实质性不同 从GBM患者髓样细胞中鉴定出的与免疫相关的LNCRNA的发现，并通过使用 纳米颗粒通过靶向这些LNCRNA来调节免疫系统。