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.

摘要 目前还没有成功的生物治疗腰椎间盘退变(IDD)。这项提案的目标是 是利用一种基于水凝胶的工程方法将PDGF输送到椎间盘(IVD)组织和 使PDGF成为一种有效的IDD抑制剂。我们还旨在定义其影响的潜在机制 使用人类IVD的正常和病变髓核(NP)和纤维环(AF)细胞以及 IDD的临床前模型。 这项拟议工作的科学前提是一系列严格的已发表证据表明，PDGF- BB和PDGF-AB在体外可刺激椎间盘细胞生长和/或抑制其程序性细胞死亡。我们的 令人信服的体内初步数据表明，PDGF-BB在兔穿刺模型中具有抗细胞凋亡的作用，该模型 从而恢复了盘的高度，并且与未处理的盘相比，提高了盘的机械性能 控制。它是基于这些令人鼓舞的数据和其他分子初步数据表明，这些 抗凋亡作用可能是通过转录因子RUNX1介导的，我们假设这是一种新的 假设NP和AF持续暴露于PDGF将通过控制抑制IDD进展 RUNX1活动。 为了验证这一假设，我们将首先比较PDGF-BB和PDGF-AB对正常和疾病的影响 高密度培养人房颤和神经节细胞。然后我们将确定潜在的分子机制 通过转录和功能分析研究PDGF对椎间盘细胞的抗退变作用 RUNX1和其他信号分子(目标1A)。RUNX1功能在PDGF介导的效应中的验证 也可以使用一种新的获得功能的小鼠模型(Aim 1B)在体内进行检查。在第二个目标中，我们将 制造和验证能够维持盘暴露的可注射生物材料的功能 细胞转化为PDGF-BB(Aim 2A)。然后，我们将在体内建立长期抑制IDD的治疗方法 PDGF-BB使用兔椎间盘穿刺术模型(目标2B)。我们提议的工作将提供开创性的信息 关于PDGF影响IVD的机制以及RUNX1在IDD中的作用。机械论 数据将有助于确定治疗IDD的新治疗靶点。