The Experts below are selected from a list of 291 Experts worldwide ranked by ideXlab platform

Zhen Huang - One of the best experts on this subject based on the ideXlab platform.

  • Harnessing region-specific neurovascular signaling to promote Germinal Matrix vessel maturation and hemorrhage prevention.
    Disease models & mechanisms, 2019
    Co-Authors: Devi Santhosh, Joe Sherman, Shafi Chowdhury, Zhen Huang
    Abstract:

    ABSTRACT Germinal Matrix hemorrhage (GMH), affecting about 1 in 300 births, is a major perinatal disease with lifelong neurological consequences. Yet despite advances in neonatal medicine, there is no effective intervention. GMH is characterized by localized bleeding in the Germinal Matrix (GM), due to inherent vessel fragility unique to this developing brain region. Studies have shown that reduced TGFβ signaling contributes to this vascular immaturity. We have previously shown that a region-specific G-protein-coupled receptor pathway in GM neural progenitor cells regulates integrin β8, a limiting activator of pro-TGFβ. In this study, we use mice to test whether this regional pathway can be harnessed for GMH intervention. We first examined the endogenous dynamics of this pathway and found that it displays specific patterns of activation. We then investigated the functional effects of altering these dynamics by chemogenetics and found that there is a narrow developmental window during which this pathway is amenable to manipulation. Although high-level activity in this time window interferes with vessel growth, moderate enhancement promotes vessel maturation without compromising growth. Furthermore, we found that enhancing the activity of this pathway in a mouse model rescues all GMH phenotypes. Altogether, these results demonstrate that enhancing neurovascular signaling through pharmacological targeting of this pathway may be a viable approach for tissue-specific GMH intervention. They also demonstrate that timing and level are likely two major factors crucial for success. These findings thus provide critical new insights into both brain neurovascular biology and the intervention of GMH.

  • A Brain-Region-Specific Neural Pathway Regulating Germinal Matrix Angiogenesis.
    Developmental Cell, 2017
    Co-Authors: Shang Ma, Devi Santhosh, T Peeyush Kumar, Zhen Huang
    Abstract:

    Summary Intimate communication between neural and vascular cells is critical for normal brain development and function. Germinal Matrix (GM), a key primordium for the brain reward circuitry, is unique among brain regions for its distinct pace of angiogenesis and selective vulnerability to hemorrhage during development. A major neonatal condition, GM hemorrhage can lead to cerebral palsy, hydrocephalus, and mental retardation. Here we identify a brain-region-specific neural progenitor-based signaling pathway dedicated to regulating GM vessel development. This pathway consists of cell-surface sphingosine-1-phosphate receptors, an intracellular cascade including Gα co-factor Ric8a and p38 MAPK, and target gene integrin β8, which in turn regulates vascular TGF-β signaling. These findings provide insights into region-specific specialization of neurovascular communication, with special implications for deciphering potent early-life endocrine, as well as potential gut microbiota impacts on brain reward circuitry. They also identify tissue-specific molecular targets for GM hemorrhage intervention.

John H. Zhang - One of the best experts on this subject based on the ideXlab platform.

  • a comprehensive review of therapeutic targets that induce microglia macrophage mediated hematoma resolution after Germinal Matrix hemorrhage
    Journal of Neuroscience Research, 2020
    Co-Authors: Jerry Flores, Damon Klebe, Jiping Tang, John H. Zhang
    Abstract:

    Currently, there is no effective treatment for Germinal Matrix hemorrhage and intraventricular hemorrhage (GMH-IVH), a common and often fatal stroke subtype in premature infants. Secondary brain injury after GMH-IVH is known to involve blood clots that contribute to inflammation and neurological deficits. Furthermore, the subsequent blood clots disrupt normal cerebrospinal fluid circulation and absorption after GMH-IVH, contributing to posthemorrhagic hydrocephalus (PHH). Clinically, GMH-IVH severity is graded on a I to IV scale: Grade I is confined to the Germinal Matrix, grade II includes intraventricular hemorrhage, grade III includes intraventricular hemorrhage with extension into dilated ventricles, and grade IV includes intraventricular hemorrhage with extension into dilated ventricles as well as parenchymal hemorrhaging. GMH-IVH hematoma volume is the best prognostic indicator, where patients with higher grades have worsened outcomes. Various preclinical studies have shown that rapid hematoma resolution quickly ameliorates inflammation and improves neurological outcomes. Current experimental evidence identifies alternatively activated microglia as playing a pivotal role in hematoma clearance. In this review, we discuss the pathophysiology of GMH-IVH in the development of PHH, microglia/macrophage's role in the neonatal CNS, and established/potential therapeutic targets that enhance M2 microglia/macrophage phagocytosis of blood clots after GMH-IVH.

  • Germinal Matrix Hemorrhage Neonatal Rat Model Using Bacterial Collagenase Injection
    Springer Series in Translational Stroke Research, 2019
    Co-Authors: Jerry Flores, Damon Klebe, Jiping Tang, John H. Zhang
    Abstract:

    Bacterial collagenase has been used to model neonatal Germinal Matrix hemorrhage and adult cerebral hemorrhage. This chapter details the bacterial collagenase injection Germinal Matrix hemorrhage neonatal rat model.

  • Bliverdin reductase-A improves neurological function in a Germinal Matrix hemorrhage rat model
    Neurobiology of disease, 2017
    Co-Authors: Yiting Zhang, Jerry Flores, Jiping Tang, Devin W. Mcbride, Yan Ding, Yixin Zhang, John H. Zhang
    Abstract:

    Germinal Matrix hemorrhage is induced by stereotaxic injection of collagenase into the Germinal Matrix of P7 Sprague-Dawley rats. Hemoglobin assay, western blot, immunofluorescence and neurobehavioral tests were used to test the effects of BLVRA on hematoma resolution and anti-inflammatory response. We showed that BLVRA triggered a signaling cascade that ameliorated post-hemorrhagic neurological deficits in both short-term and long-term neurobehavioral tests in a GMH rat model. Specifically, BLVRA inhibited toll-like receptor 4 (TLR4) expression by translocating to the nucleus in an endothelial nitric oxide (eNOS)/nitric oxide (NO)-dependent manner. BLVRA also induced the upregulation of CD36 scavenger receptor level in microglia/microphages, of which the prominent role is to enhance hematoma resolution. However, the beneficial effects of BLVRA were abolished with the knockdown of eNOS, indicating that the eNOS/NO system is an important downstream factor of BLVRA. Our results demonstrate a mechanism of BLVRA modulating hematoma resolution and suppressing inflammation through eNOS/NO/TLR4 pathway in the GMH rat model.

  • pparγ induced upregulation of cd36 enhances hematoma resolution and attenuates long term neurological deficits after Germinal Matrix hemorrhage in neonatal rats
    Neurobiology of Disease, 2016
    Co-Authors: Jerry Flores, Damon Klebe, Tim Lekic, Paul R. Krafft, William Rolland, John H. Zhang
    Abstract:

    Germinal Matrix hemorrhage remains the leading cause of morbidity and mortality in preterm infants in the United States with little progress made in its clinical management. Survivors are often afflicted with long-term neurological sequelae, including cerebral palsy, mental retardation, hydrocephalus, and psychiatric disorders. Blood clots disrupting normal cerebrospinal fluid circulation and absorption after Germinal Matrix hemorrhage are thought to be important contributors towards post-hemorrhagic hydrocephalus development. We evaluated if upregulating CD36 scavenger receptor expression in microglia and macrophages through PPARγ stimulation, which was effective in experimental adult cerebral hemorrhage models and is being evaluated clinically, will enhance hematoma resolution and ameliorate long-term brain sequelae using a neonatal rat Germinal Matrix hemorrhage model. PPARγ stimulation (15d-PGJ2) increased short-term PPARγ and CD36 expression levels as well as enhanced hematoma resolution, which was reversed by a PPARγ antagonist (GW9662) and CD36 siRNA. PPARγ stimulation (15d-PGJ2) also reduced long-term white matter loss and post-hemorrhagic ventricular dilation as well as improved neurofunctional outcomes, which were reversed by a PPARγ antagonist (GW9662). PPARγ-induced upregulation of CD36 in macrophages and microglia is, therefore, critical for enhancing hematoma resolution and ameliorating long-term brain sequelae.

  • Intranasal Osteopontin for Rodent Germinal Matrix Hemorrhage
    Acta neurochirurgica. Supplement, 2016
    Co-Authors: Jay Malaguit, Jiping Tang, John H. Zhang, Darlene Casel, Brandon J. Dixon, Desislava Doycheva, Tim Lekic
    Abstract:

    Germinal Matrix hemorrhage (GMH) is the most common and devastating neurological problem of premature infants. Current treatment is largely ineffective and GMH has been nonpreventable. Osteopontin (OPN) is an endogenous protein that has been shown to be neuroprotective, however, it has not been tested in GMH. P7 neonatal rats were subjected to stereotactic ganglionic eminence collagenase infusion. Groups were as follows: (1) sham, (2) GMH + vehicle, (3) GMH + intranasal OPN. Seventy-two hours later, the animals were evaluated using righting reflex, blood-brain barrier (BBB) permeability by Evans blue dye leakage, brain water content, and hemoglobin assay. Intranasal OPN improved outcomes after GMH by attenuation of brain swelling, BBB function, re-bleeding, and neurological outcomes. OPN may play an important role in enhancing neuroprotective brain signaling following GMH. These observed effects may offer novel possibilities for therapy in this patient population.

Devi Santhosh - One of the best experts on this subject based on the ideXlab platform.

  • Harnessing region-specific neurovascular signaling to promote Germinal Matrix vessel maturation and hemorrhage prevention.
    Disease models & mechanisms, 2019
    Co-Authors: Devi Santhosh, Joe Sherman, Shafi Chowdhury, Zhen Huang
    Abstract:

    ABSTRACT Germinal Matrix hemorrhage (GMH), affecting about 1 in 300 births, is a major perinatal disease with lifelong neurological consequences. Yet despite advances in neonatal medicine, there is no effective intervention. GMH is characterized by localized bleeding in the Germinal Matrix (GM), due to inherent vessel fragility unique to this developing brain region. Studies have shown that reduced TGFβ signaling contributes to this vascular immaturity. We have previously shown that a region-specific G-protein-coupled receptor pathway in GM neural progenitor cells regulates integrin β8, a limiting activator of pro-TGFβ. In this study, we use mice to test whether this regional pathway can be harnessed for GMH intervention. We first examined the endogenous dynamics of this pathway and found that it displays specific patterns of activation. We then investigated the functional effects of altering these dynamics by chemogenetics and found that there is a narrow developmental window during which this pathway is amenable to manipulation. Although high-level activity in this time window interferes with vessel growth, moderate enhancement promotes vessel maturation without compromising growth. Furthermore, we found that enhancing the activity of this pathway in a mouse model rescues all GMH phenotypes. Altogether, these results demonstrate that enhancing neurovascular signaling through pharmacological targeting of this pathway may be a viable approach for tissue-specific GMH intervention. They also demonstrate that timing and level are likely two major factors crucial for success. These findings thus provide critical new insights into both brain neurovascular biology and the intervention of GMH.

  • A Brain-Region-Specific Neural Pathway Regulating Germinal Matrix Angiogenesis.
    Developmental Cell, 2017
    Co-Authors: Shang Ma, Devi Santhosh, T Peeyush Kumar, Zhen Huang
    Abstract:

    Summary Intimate communication between neural and vascular cells is critical for normal brain development and function. Germinal Matrix (GM), a key primordium for the brain reward circuitry, is unique among brain regions for its distinct pace of angiogenesis and selective vulnerability to hemorrhage during development. A major neonatal condition, GM hemorrhage can lead to cerebral palsy, hydrocephalus, and mental retardation. Here we identify a brain-region-specific neural progenitor-based signaling pathway dedicated to regulating GM vessel development. This pathway consists of cell-surface sphingosine-1-phosphate receptors, an intracellular cascade including Gα co-factor Ric8a and p38 MAPK, and target gene integrin β8, which in turn regulates vascular TGF-β signaling. These findings provide insights into region-specific specialization of neurovascular communication, with special implications for deciphering potent early-life endocrine, as well as potential gut microbiota impacts on brain reward circuitry. They also identify tissue-specific molecular targets for GM hemorrhage intervention.

Ruben Mühl-benninghaus - One of the best experts on this subject based on the ideXlab platform.

  • Superficial Siderosis after Germinal Matrix Hemorrhage.
    American Journal of Neuroradiology, 2016
    Co-Authors: Umut Yilmaz, Sascha Meyer, Heiko Körner, Meltem Turkyilmaz, Andreas Simgen, Wolfgang Reith, Ludwig Gortner, Ruben Mühl-benninghaus
    Abstract:

    BACKGROUND AND PURPOSE: Germinal Matrix hemorrhage is a frequent complication of prematurity and can be associated with adverse neurodevelopmental outcome, depending on its severity. In addition to parenchymal damage, intraventricular residues of hemorrhage and hydrocephalus MR imaging findings include superficial siderosis. The purpose of this study was to investigate the prevalence and location of superficial siderosis in patients with a history of Germinal Matrix hemorrhage. MATERIALS AND METHODS: We retrospectively identified patients with a history of Germinal Matrix hemorrhage who underwent MR imaging in our institution between 2008 and 2016. Imaging was evaluated for the presence and location of superficial siderosis. The presence of subependymal siderosis and evidence of hydrocephalus were assessed. RESULTS: Thirty-seven patients with a history of Germinal Matrix hemorrhage were included; 86.5% had preterm births. The mean age at the first MR imaging was 386 days (range 2–5140 days). The prevalence of superficial siderosis was 67.6%. Superficial siderosis was detected significantly more often when MR imaging was performed within the first year of life (82.8% versus 12.5%, P CONCLUSIONS: Here we report that superficial siderosis is a common MR imaging finding in the first year of life of patients with a history of Germinal Matrix hemorrhage, but it dissolves and has a low prevalence thereafter. A prospective analysis of its initial severity and speed of dissolution during this first year might add to our understanding of the pathophysiology of neurodevelopmental impairment after Germinal Matrix hemorrhages.

William R. Brown - One of the best experts on this subject based on the ideXlab platform.

  • Immunolocalization of tight junction proteins in blood vessels in human Germinal Matrix and cortex.
    Histochemistry and cell biology, 2006
    Co-Authors: John A. Anstrom, Dixon M. Moody, Clara R. Thore, William R. Brown
    Abstract:

    Brain development occurs in a specialized environment maintained by a blood–brain barrier (BBB). An important structural element of the BBB is the endothelial tight junction (TJ). TJs are present during the embryonic period, but BBB impermeability accrues over an extended gestational interval. In studies of human premature infants, we used immunomicroscopy to determine if amounts of the TJ proteins ZO-1, claudin and occludin increase with gestational age in vessels of Germinal Matrix (GM) and cortex. By 24 weeks postconception (PC), TJ proteins were present in both GM and cortical vessels, but immunoreactivity in the GM of the youngest subjects was less than in older subjects. At 24 weeks PC, TJ protein immunoreactivity in GM vessels was less than in cortical vessels suggesting that TJ maturation progresses along a superficial to deep brain axis. This concept correlates with conclusions from previous analyses of the expression of brain endothelial cell alkaline phosphatase (AP) activity. AP appears in cortical vessels before appearing in deep white matter and GM vessels. Together, these data indicate that differentiation of some functional specializations is still in progress in GM vessels during the third trimester. This maturation could relate to the pathogenesis of Germinal Matrix hemorrhage–intraventricular hemorrhage.

  • Morphometric assessment of collagen accumulation in Germinal Matrix vessels of premature human neonates.
    Neuropathology and applied neurobiology, 2005
    Co-Authors: John A. Anstrom, Dixon M. Moody, Steven M. Block, Venkata R. Challa, Clara R. Thore, William R. Brown
    Abstract:

    Germinal Matrix haemorrhage in premature neonates is commonly attributed to vascular immaturity, possibly related to an abbreviated process of angiogenesis. Terminal steps in the progression of angiogenesis are the formation of a subendothelial basal lamina containing collagen IV and an extracellular Matrix containing collagens I and III. Immature vessels would predictably be deficient in these collagen subtypes. We analysed Germinal Matrix (GM), cortical, and white matter (WM) vessels with antibodies specific for collagens I, III and IV to test the hypothesis that GM vessels are immature. Brains were collected during post-mortem from prematurely born human neonates ranging in age from 17 weeks to 36 weeks postconception. All GM vessels were immunoreactive for collagen subtypes I, III and IV. Using digital image analysis, collagen IV immunoperoxidase-labelling was measured in vessels in GM, cortex and WM. Intensity values in GM and WM were normalized relative to cortical intensity within the same subject. At week 17 of gestation, GM vessels exhibited a higher concentration of collagen IV than did WM or cortical vessels. Regression analysis demonstrated that collagen intensity in GM was greater than that in cortex and WM at all stages. We conclude that GM vessels in even the youngest, prematurely born, viable neonates do not exhibit evidence of structural immaturity. The high incidence of GM haemorrhage in premature neonates may be related to factors other than a deficiency in accumulated collagen.

  • Human Germinal Matrix: venous origin of hemorrhage and vascular characteristics.
    AJNR. American journal of neuroradiology, 1997
    Co-Authors: Hani S. Ghazi-birry, William R. Brown, Dixon M. Moody, V. R. Challa, S M Block, David M. Reboussin
    Abstract:

    PURPOSE To examine the vascular supply and architecture of the Germinal Matrix in the preterm neonatal brain and to determine whether veins or arterioles are the source of Germinal Matrix hemorrhage. METHODS Brains from eight preterm neonates (24 to 35 weeks9 gestation) and two full-term infants were fixed in alcohol, embedded in celloidin, sectioned at 100- and 500-micron thicknesses, stained for alkaline phosphatase, and examined with light microscopy. High-resolution contact radiographs of 500-micron-thick sections were also mounted on glass slides for microscopic examination. RESULTS The upper and middle regions of the Germinal Matrix are supplied by branches of the lateral striate arteries, whereas the inferior part is supplied by branches of the recurrent artery of Heubner. In brain sections from four of the preterm infants, we found 15 circumscribed hemorrhagic foci within the Germinal Matrix. The largest was 5 mm in diameter; the smallest, 1 mm. All hemorrhages but one were closely associated with veins, with significant involvement of the perivenous space. The other hemorrhage appeared to be associated with an arteriole. In term and preterm infants, we found no arteriolar-to-arteriolar shunts, precapillary arteriolar-to-venules shunts, or vascular rete. At all gestational ages, the terminal vascular bed had only conventional branchings and connections. CONCLUSION In preterm neonates, staining for endogenous alkaline phosphatase allows visual differentiation between afferent and efferent vessels. Germinal Matrix hemorrhage in preterm neonates is primarily venous in origin. A hemorrhage can tunnel along the venous perivascular space, collapsing the vein and rupturing the tethered connecting tributaries. Extravasation of blood from the arterial circulation appears to be much less common.

  • Germinal Matrix HEMORRHAGE (GMH) LOCATION IN VERY LOW BIRTH WEIGHT (VLBW) NEONATES. † 1166
    Pediatric Research, 1996
    Co-Authors: Steven M. Block, Hani S. Ghazi-birry, William R. Brown, Dixon M. Moody, Venkata R. Challa, Nancy Peters
    Abstract:

    Germinal Matrix HEMORRHAGE (GMH) LOCATION IN VERY LOW BIRTH WEIGHT (VLBW) NEONATES. † 1166