Control of intervertebral disc degeneration via matrix-mediated delivery of platelet-derived growth factors

通过基质介导的血小板衍生生长因子的传递来控制椎间盘退变

• 批准号: 10614929
• 负责人: HICHAM M DRISSI
• 金额: $ 42.28万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614929
• 关键词: Aftercare; Apoptosis; Apoptotic; Autophagocytosis; Autopsy; Back Pain; Becaplermin; Biocompatible Materials; Biological Assay; Biological Response Modifier Therapy; Biomechanics; Blood Platelets; Cells; Chondrocytes; Clinical; Collagen; Complementary DNA; Cytokeratin; Data; Data Analyses; Databases; Disease; Dose; Drug Delivery Systems; Economic Burden; Encapsulated; Engineering; Exposure to; FGF2 gene; GAG Gene; Gene Expression; Generations; Genes; Genetic Transcription; Goals; Growth Factor; Height; Histologic; Histology; Homeostasis; Human; Hydrogels; Image; In Vitro; Induction of Apoptosis; Injectable; Insulin-Like Growth Factor I; Intervertebral disc structure; Lasers; Light; Link; Literature; Low Back Pain; LoxP-flanked allele; Magnetic Resonance Imaging; Measures; Mediating; Messenger RNA; Microscopy; Modality; Modeling; Molecular; Mus; Neck Pain; Operative Surgical Procedures; Orthopedics; Oryctolagus cuniculus; Outcome; Outcome Measure; Pathway Analysis; Plasma; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor alpha Receptor; Platelet-Derived Growth Factor beta Receptor; Pre-Clinical Model; Prevalence; Process; Production; Public Health; Publishing; Puncture procedure; RUNX1 gene; Reporting; Repression; Research; Role; Seminal; Serum; Signal Transduction; Signaling Molecule; Societies; Starvation; Sulfate; Symptoms; Tail; Testing; Therapeutic; Therapeutic Effect; Tissues; Transforming Growth Factor beta; Transgenic Organisms; Treatment Efficacy; Validation; Work; cell growth; defined contribution; density; disability; gain of function; global health; human disease; improved; in vivo; inhibitor; intervertebral disk degeneration; knock-down; laser capture microdissection; mechanical properties; monolayer; mouse model; new therapeutic target; novel; nucleus pulposus; overexpression; platelet-derived growth factor AB; platelet-derived growth factor BB; preclinical study; promoter; response; second harmonic; senescence; single-cell RNA sequencing; small hairpin RNA; societal costs; transcription factor; transcriptomics

Summary There is no successful biologic treatment for intervertebral disc degeneration (IDD). The goal of this proposal is to utilize a hydrogel-based engineering approach to deliver PDGF to intervertebral disc (IVD) tissue and establish PDGF as a potent inhibitor of IDD. We also aim to define the mechanisms underlying its effects on normal and diseased nucleus pulposus (NP) and annulus fibrosus (AF) cells using human IVDs as well as preclinical models of IDD. The scientific premise for the proposed work is a rigorous body of published evidence demonstrating that PDGF- BB, as well as PDGF-AB can stimulate disc cell growth and/or inhibit their programmed cell death in vitro. Our compelling preliminary data in vivo point to an anti-apoptotic effect of PDGF-BB in a rabbit puncture model, which led to restored disc height and enhanced mechanical properties of the treated discs compared to untreated controls. It is based on these encouraging data and other molecular preliminary data demonstrating that these anti-apoptotic effects may be mediated through the transcription factor Runx1, that we postulate the novel hypothesis that sustained exposure of the NP and AF to PDGF will repress IDD progression through controlling Runx1 activity. To test this hypothesis, we will first compare the effects of PDGF-BB and PDGF-AB on normal versus diseased human AF and NP cells cultured in high density. We will then determine the molecular mechanisms underlying the anti-degenerative effects of PDGF on disc cells through transcriptomic and functional analyses involving RUNX1 and other signaling molecules (Aim 1A). The validation of Runx1 function in PDGF-mediated effects will also be examined in vivo using a new gain of function mouse model (Aim 1B). In the second Aim, we will fabricate and validate the functionality of an injectable biomaterial capable of sustaining the exposure of disc cells to PDGF-BB (Aim 2A). We will then establish therapeutic modalities for long-term inhibition of IDD in vivo by PDGF-BB using a rabbit disc puncture model (Aim 2B). Our proposed work will provide seminal information about the mechanisms underlying PDGF’s effects on the IVD and the role of Runx1 in IDD. The mechanistic data will help identify new therapeutic targets to treat IDD.

概括 椎间盘变性（IDD）没有成功的生物治疗。该提议的目标 是利用基于水凝胶的工程方法将PDGF运送到椎间盘（IVD）组织和 建立PDGF作为IDD的潜在抑制剂。我们还旨在定义其对其对影响的机制 使用人IVD以及 IDD的临床前模型。 拟议工作的科学前提是严格的公开证据，表明PDGF- BB以及PDGF-AB可以刺激椎间盘细胞的生长和/或在体外抑制其程序性细胞死亡。我们的 在体内引人入胜的初步数据指向兔穿刺模型中PDGF-BB的抗凋亡效应 与未经处理 控件。它基于这些令人鼓舞的数据和其他分子初步数据，表明这些数据 抗凋亡作用可以通过转录因子runx1介导，我们假设新颖 假设NP和AF持续暴露于PDGF将通过控制来抑制IDD的进展 Runx1活动。 为了检验这一假设，我们将首先比较PDGF-BB和PDGF-AB对正常与解散的影响 人AF和NP细胞以高密度培养。然后，我们将确定基础的分子机制 通过涉及的转录组和功能分析，PDGF对椎间盘细胞的抗降低作用 RUNX1和其他信号分子（AIM 1A）。 PDGF介导的效果中RUNX1函数的验证将 也可以使用新功能鼠标模型在体内检查（AIM 1B）。在第二个目标中，我们将 捏造和验证能够维持光盘暴露的可注射生物材料的功能 细胞到PDGF-BB（AIM 2A）。然后，我们将建立用于长期抑制体内IDD的治疗方式 通过PDGF-BB使用兔子盘穿刺模型（AIM 2B）。我们建议的工作将提供第二个信息 关于PDGF对IVD的影响和Runx1在IDD中的作用的机制。机制 数据将有助于确定新的治疗目标以治疗IDD。