Harness Germinal Matrix Hemorrhage

描述（由申请方提供）：老年基质出血（GMH）定义为室管膜下脑组织内未成熟血管破裂。GMH约占每1 000名新生儿中3.5人，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，一种凝血因子，由颅内出血激活。凝血酶引发炎症反应、神经胶质增生和细胞外基质（ECM）蛋白的过度产生，从而阻塞脑室系统并损害CSF引流。凝血酶通过激活G蛋白偶联受体的一个亚家族，即蛋白酶激活受体（PARs），参与瘢痕组织的增殖。一旦受到刺激，PAR将激活mTOR，据报道，mTOR会诱导ECM蛋白的过度产生，从而导致阻塞和CSF引流受损。我们的第一个推论假设是，通过阻断PAR及其下游靶点，GMH后脑积水将减少。凝血酶还将导致脑室内和脑室内血块的形成，其机械地损害CSF的循环和吸收，从而导致GMH后脑积水的形成。我们的第二个推论假设是，通过巨噬细胞活化增强血凝块的溶解和清除，将有效地减少GMH后的脑积水和随之而来的神经功能缺损。我们将实施过氧化物酶体增殖物激活受体γ（PPAR-？）的药理学激活，据报道，其可增加红细胞的小胶质细胞吞噬作用，从而减小残余凝块的大小。 根据现有的成人脑出血文献和我们自己在实验性GMH后的初步观察，我们建议描述GMH诱导的脑损伤的程度，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（PAR和mTOR）和凝块清除（通过PPAR-？）将减少GMH诱导的脑积水并改善该新生GMH大鼠模型中的长期神经功能。我们将评估PAR和PPAR-？关于GMH病理学和治疗，目的如下：目的1将在新的GMH大鼠模型中研究凝血酶和凝块形成在出血后脑积水中的作用。 我们假设GMH血凝块会损害CSF循环，凝血酶活性增加会促进细胞外基质增殖，导致正常CSF动力学紊乱，并发展为脑积水和长期神经功能缺损。 目的2探讨凝血酶下游效应子（PARs和mTOR）在GMH诱导脑积水中的作用。 我们假设凝血酶激活PAR将通过mTOR激活导致细胞外基质蛋白过度产生，从而阻碍CSF引流并诱导脑积水。PAR抑制将减少细胞外基质增殖和脑积水。 目标3将确定的作用，过氧化物酶体增殖物激活受体-？GMH后的血凝块清除率 我们假设过氧化物酶体增殖物激活受体-？激活将激活红细胞的小胶质细胞吞噬作用，从而减少血凝块和脑积水。该提案的长期目标是为GMH患者提供非侵入性治疗方法。

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.