Harness Germinal Matrix Hemorrhage

利用生发基质出血

• 批准号: 8443073
• 负责人: John H Zhang
• 金额: $ 34.56万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443073
• 关键词: Adult; Affect; Antioxidants; Binding; Birth; Blood Circulation; Blood Clot; Blood Coagulation Factor; Blood Vessels; Blood coagulation; Brain; Brain Injuries; Brain hemorrhage; Caring; Cerebral hemisphere hemorrhage; Cerebrospinal Fluid; Cicatrix; Clinical Management; Coagulation Process; Communities; Development; Drainage procedure; Educational process of instructing; Erythrocytes; Extracellular Matrix; Extracellular Matrix Proteins; G-Protein-Coupled Receptors; Genetic Transcription; Gliosis; Goals; Hemorrhage; Hydrocephalus; Impairment; Inflammatory; Inflammatory Response; Injury; Intraventricular; Lead; Link; Literature; Macrophage Activation; Mechanics; Mediating; Metabolic; Modeling; Morbidity - disease rate; Names; Neonatal; Nervous System Physiology; Neurologic; Newborn Infant; Nuclear Hormone Receptors; Obstruction; Operative Surgical Procedures; Outcome; PAR-1 Receptor; PPAR gamma; Parents; Pathology; Pathway interactions; Patients; Perinatal subependymal hemorrhage; Peritoneum; Peroxisome Proliferator-Activated Receptors; Phagocytosis; Pharmacological Treatment; Phosphorylation; Premature Infant; Procedures; Protein-Serine-Threonine Kinases; Proteinase-Activated Receptors; Proteins; Rattus; Receptor Inhibition; Reporting; Residual state; Resolution; Response Elements; Role; Rupture; Shunt Device; Subependymal; Surgical complication; System; Testing; Therapeutic; Thrombin; Time; Tissues; United States; Water; absorption; brain tissue; cerebral atrophy; design; disability; human FRAP1 protein; improved; killings; member; mortality; neurobehavioral; novel; treatment strategy

DESCRIPTION (provided by applicant): Germinal matrix hemorrhage (GMH) is defined as the rupture of immature blood vessels within the subependymal brain tissue. Occurring in approximately 3.5 per 1,000 births, GMH presents a leading cause of mortality and morbidity in premature infants. Debilitating consequences of GMH include the formation of post- hemorrhagic hydrocephalus, leading to brain atrophy and neurological impairments. A major causative factor of hydrocephalus formation is thrombin, a coagulation factor, activated by the intracranial bleed. Thrombin initiates inflammatory responses, gliosis and overproduction of extracellular matrix (ECM) proteins, which obstruct the cerebroventricular system and impair CSF drainage. Thrombin participates in the proliferation of scar tissue by activating a subfamily of G protein-coupled receptors, named proteinase-activated-receptors (PARs). Once stimulated, PARs will activate mTOR, which has been reported to induce overproduction of ECM proteins, thus resulting in obstruction and impaired CSF drainage. Our first corollary hypothesis is that by blocking PARs and their downstream targets, hydrocephalus will be reduced after GMH. Thrombin will also lead to the formation of peri- and intraventricular blood clots, which mechanically impair the circulation and absorption of CSF, thus leading to hydrocephalus formation after GMH. Our second corollary hypothesis is that enhancing blood clot resolution and clearance, via macrophage activation, will effectively reduce hydrocephalus and consequent neurological deficits after GMH. We will implement pharmacological activation of peroxisome proliferator-activated receptor gamma (PPAR-?), which has been reported to increase microglial phagocytosis of red blood cells, thus decreasing residual clot sizes. From existing literature on adult intracerebral hemorrhage and from our own preliminary observations after experimental GMH, we propose to characterize the extent of GMH-induced brain injury and provide novel non- invasive therapeutic strategies. Our central hypothesis is that targeting thrombin downstream effectors (PARs & mTOR) and clot clearance (via PPAR-?) will reduce GMH-induced hydrocephalus and improve long term neurological function in this neonatal GMH rat model. We will evaluate the implication of PARs and PPAR-? with respect to GMH pathology and therapy in the following aims: Aim 1 will investigate the role of thrombin and clot formation in post-hemorrhagic hydrocephalus in a novel GMH rat model. We hypothesize that GMH blood clots will impair the CSF circulation and an increase of thrombin activity will promote extracellular matrix proliferation, leading to disturbances in normal CSF dynamics and the development of hydrocephalus and long-term neurological deficits. Aim 2 will determine the role of thrombin downstream effectors (PARs & mTOR) in GMH induced hydrocephalus. We hypothesize that the activation of PARs by thrombin will cause the overproduction of extracellular matrix proteins, via mTOR activation, thus obstructing CSF drainage and inducing hydrocephalus. PAR inhibition will reduce extracellular matrix proliferation and hydrocephalus. Aim 3 will determine the role of PPAR-? in clot clearance after GMH. We hypothesize that PPAR-? activation will activate microglial phagocytosis of red blood cells, hence reducing blood clots and hydrocephalus. The long-term goals of this proposal are to provide non-invasive therapeutic approaches for GMH patients. PUBLIC HEALTH RELEVANCE: One in every 300 newborn babies in the United States will have bleeding inside the brain tissues during or immediately after labor. This bleeding may either kill or cause lifelong disabilities that will not only affect the baby but also impact the lves of parents, and communities that raise, teach and care for them. This proposal will answer why bleeding in the brain causes water accumulation (hydrocephalus) which damages surrounding brain tissues and leads to long term disability. Current surgical treatment (shunting) is invasive and ineffective. Our proposed non-invasive pharmacological treatment strategies if proved beneficial, will potentially impact the clinical management of this devastating condition.

描述(申请人提供)：生发基质出血(GMH)被定义为室管膜下脑组织内未成熟血管的破裂。GMH的发病率约为3.5‰，是早产儿死亡和发病的主要原因。GMH的衰弱后果包括形成出血后脑积水，导致脑萎缩和神经损伤。脑积水形成的一个主要原因是凝血酶，一种被颅内出血激活的凝血因子。凝血酶可引起炎症反应、胶质化和细胞外基质(ECM)蛋白的过度产生，从而阻塞脑室系统，损害脑脊液引流。凝血酶通过激活G蛋白偶联受体亚家族参与瘢痕组织的增殖，称为蛋白酶激活受体(PARs)。一旦受到刺激，PAR将激活mTOR，据报道，mTOR可诱导ECM蛋白过度生产，从而导致脑脊液引流障碍和障碍。我们的第一个推论是，通过阻断PARs及其下游靶点，GMH后脑积水将会减少。凝血酶还会导致脑室周围和脑室内血栓的形成，从而机械地损害脑脊液的循环和吸收，从而导致GMH后脑积水的形成。我们的第二个推论是，通过巨噬细胞激活提高血块的分解和清除，将有效地减少GMH后的脑积水和随之而来的神经功能障碍。我们将实施过氧化物酶体增殖物激活受体-γ(PPAR-？)的药理激活，据报道，PPAR-？可以增加小胶质细胞对红细胞的吞噬能力，从而减少残余血栓大小。根据现有的关于成人脑出血的文献和我们自己在实验性GMH后的初步观察，我们建议表征GMH引起的脑损伤的程度，并提供新的非侵入性治疗策略。我们的中心假设是靶向凝血酶下游效应物(PARS&mTOR)和凝块清除(通过PPAR-？)将减少GMH诱导的脑积水，并改善这种新生GMH大鼠模型的长期神经功能。我们将评估PARS和PPAR-？就GMH的病理和治疗而言，目的如下：目的1在一种新的GMH大鼠模型中，研究凝血酶和凝块形成在出血性脑积水中的作用。我们假设GMH血凝块将损害脑脊液循环，凝血酶活性的增加将促进细胞外基质的增殖，导致正常脑脊液动力学的紊乱，并发展为脑积水和长期的神经功能障碍。目的2将确定凝血酶下游效应因子(PARS&mTOR)在GMH诱导的脑积水中的作用。我们推测凝血酶激活PARs将通过激活mTOR导致细胞外基质蛋白的过度产生，从而阻碍脑脊液引流，从而导致脑积水。抑制PAR会减少细胞外基质的增殖和脑积水。目标3将决定PPAR-？在GMH后清除血块。我们假设PPAR-？激活会激活小胶质细胞对红细胞的吞噬作用，从而减少血栓和脑积水。该提案的长期目标是为GMH患者提供非侵入性治疗方法。 与公共卫生相关：在美国，每300名新生儿中就有一名在分娩期间或产后立即出现脑组织内出血。这种出血可能会导致死亡或终身残疾，这不仅会影响婴儿，还会影响父母的左肺功能，以及抚养、教育和照顾他们的社区。这项建议将回答为什么大脑出血会导致积水(脑积水)，这会损害周围的脑组织，并导致长期残疾。目前的外科治疗(分流术)是侵入性的且无效。我们提出的非侵入性药物治疗策略如果被证明是有益的，将潜在地影响这种毁灭性疾病的临床治疗。