Use of Multifunctional rhPRG4 Biologic for Treatment of TBI

多功能rhPRG4生物制剂用于治疗TBI

• 批准号: 9223371
• 负责人: ADAM CHODOBSKI
• 金额: $ 22.81万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223371
• 关键词: Acute; Adhesives; Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Bathing; Binding; Blood - brain barrier anatomy; Brain; Brain Injuries; CD44 gene; Cartilage; Cells; Chronic Phase; Clinical; Clinical Trials; Data; Dose; Drug Kinetics; Edema; Equilibrium; Exhibits; Eye diseases; Galectin 3; Glycoproteins; Goals; Hospitalization; Hour; Human; Hydrophobic Surfaces; Inflammatory; Injury; Lead; Ligands; MAP Kinase Gene; MMP9 gene; Matrix Metalloproteinases; Mediator of activation protein; Medical; Memory Loss; Memory impairment; Modeling; Molecular Weight; Mucinous; Nervous System Trauma; Neurological outcome; Neuroprotective Agents; Outcome; Pathologic Processes; Pathology; Patients; Peptide Hydrolases; Permeability; Pharmacodynamics; Phase; Plasma; Play; Positioning Attribute; Process; Production; Property; Proteins; Proteoglycan; Rattus; Recombinants; Recovery of Function; Severities; Signal Transduction; Staging; Surrogate Markers; TBI Patients; Testing; Therapeutic; Therapeutic Effect; Therapeutic Uses; Tight Junctions; Tissues; Toll-like receptors; Trauma; Traumatic Brain Injury; Traumatic Brain Injury recovery; Treatment Efficacy; Walking; base; biomarker evaluation; brain parenchyma; clinical application; cognitive function; controlled cortical impact; design; disability; effective therapy; executive function; eye dryness; functional outcomes; improved; injured; innovation; lubricin; morris water maze; mortality; motor deficit; multidisciplinary; neurobehavioral; neurobehavioral test; neuroinflammation; neuron loss; novel; outcome forecast; pre-clinical; relating to nervous system; research study; scale up; therapeutic development

PROJECT SUMMARY Traumatic brain injury (TBI) is a devastating medical condition that affects more than 1.7 million civilians in the US and represents an unmet clinical need. Effective therapies are urgently needed, as TBI is associated with high rates of hospitalization, mortality, and disability. Previous clinical trials have failed to demonstrate thera- peutic efficacy in patients with TBI. This project focuses on evaluating the therapeutic efficacy of a novel multifunctional biologic—recombinant human proteoglycan 4 (rhPRG4), also known as lubricin—in TBI. rhPRG4 effectively interacts with both hydrophilic and hydrophobic surfaces, and has strong anti-adhesive and anti-inflammatory properties. When administered peripherally in a rat model of TBI, rhPRG4 crosses the blood-brain barrier (BBB) in the injured brain parenchyma, but is absent from the uninjured parts of the brain. Our preliminary data show that rhPRG4 dramatically decreases the post-traumatic production of proinflammatory mediators and matrix metallo- proteinases, and reduces the influx of inflammatory cells into the injured brain parenchyma. rhPRG4 also has a unique ability to stabilize the BBB, whose function is affected by TBI. These observations suggest that the rhPRG4 biologic could limit the destruction of neural tissue observed in TBI and, consequently, improve neurological outcome after injury. There are two major goals of this study: (1) to assess the efficacy of rhPRG4 in engaging with its putative targets and enhance our understanding of rhPRG4's ability to stabilize the BBB in acute phase of injury, and (2) to obtain preclinical data on long-term efficacy of rhPRG4 in reducing the neuronal loss and improving functional outcome after TBI.

项目摘要 创伤性脑损伤（TBI）是一种毁灭性的医疗状况，影响着美国170多万平民。 美国，代表未满足的临床需求。迫切需要有效的治疗，因为TBI与 高住院率、死亡率和残疾率。以前的临床试验未能证明治疗- TBI患者的治疗效果。 本项目的重点是评价一种新型多功能生物重组体的治疗效果 人蛋白聚糖4（rhPRG 4），也称为润滑素TBI。rhPRG 4有效地与 亲水性和疏水性表面，并具有很强的防粘和抗炎性能。当 在TBI大鼠模型中外周给药，rhPRG 4穿过损伤的血脑屏障（BBB）。 脑实质，但不存在于大脑的未受伤部分。我们的初步数据显示rhPRG 4 显著降低创伤后促炎介质和基质金属的产生， 蛋白酶，并减少炎性细胞流入受伤的脑实质。rhPRG 4还具有 稳定BBB的独特能力，其功能受TBI影响。这些观察表明， rhPRG 4生物制剂可以限制在TBI中观察到的神经组织的破坏，从而改善TBI中神经组织的损伤。 损伤后的神经功能。 本研究有两个主要目的：（1）评估rhPRG 4在参与其假定的细胞增殖中的功效。 靶向并增强我们对rhPRG 4在损伤急性期稳定BBB的能力的理解， (2)获得rhPRG 4在减少神经元丢失和改善神经元损伤方面的长期疗效的临床前数据 TBI后的功能结果。