As many as 50% of low-birth-weight infants suffer cognitive deficits due to chronic hypoxia and circulatory complications. Longitudinal studies suggest recovery in both brain volume and cognitive functions by early adulthood in some children, however this recovery is variable and the neurobiological basis of this improvement are not understood. Our mouse model of chronic sublethal hypoxic injury reproduces the initial cortical volume deficit and ventriculomegaly, as well as the subsequent recovery, although some neuron loss and cognitive abnormalities persist long-term in these mice. Identifying tlie cellular and molecular events that underlie neuronal recovery and finding ways to enhance this process are the common goals of this program project. We hypothesize that recovery from hypoxic brain injury is due to a coupled neurogenic/angiogenic response. This includes (1) proliferation of neural stem cells and progenitors, which requires specific growth factors in neural stem cells and vascular endothelium;(2) survival of newly-born neuronal and glial populations, which requires improved energetic metabolism in the newly-generated cells and trophic influences from neural and vascular compartments. Specific projects in this program will test these hypotheses by generating tissue-specific and time-dependent loss- or gain-of function genetic models to test the function of several proliferative, survival and differentiation factors in neural stem cells, oligodendrocyte progenitors, and vascular endothelium. The factors under investigation include Fibroblast growth factor 2 (FGF2), the Epidermal growth factor receptor (EGFR), TrkB and its ligand Brain derived neurotropic growth factor (BDNF), the mitochondrial uncoupling protein 2 (UCP2) and the gut hormone ghrelin. Elucidating the role of these genes in specific cell types will reveal the reciprocal and dynamic interactions between vascular, neural and metabolic components as the animals recover from injury in standard or enriched environment. A multidisciplinary approach, which includes morphometric and immunocytochemical analyses, electron microscopy and electrophysiology, is used to assess whether the signaling systems under study contribute adaptive changes triggered by the enriched environment in hypoxic animals. Furthermore, the beneficial effect of enhancing specific components of these signaling systems will be tested at the cellular and behaviorallevel. The long-term goal of these studies is to identify new means of therapeutic intervention to decrease the developmental disability and neurobehavioral sequelae of preterm birth.
Preterm birth is one of the major pediatric public health problems of our time. The goal of this P01 is to identify the adaptive mechanisms that underlie the anatomical and behavioral recovery that occurs in some of these children. This will permit to enhance these mechanisms in those who cannot recover, identifying new means of therapeutic intervention to decrease the neurobehavioral sequelae of preterm birth. This will be approached under the auspices of four interrelated projects and two cores, all using our mouse model of sublethal hypoxic injury.
|Kuwahara, Go; Hashimoto, Takuya; Tsuneki, Masayuki et al. (2017) CD44 Promotes Inflammation and Extracellular Matrix Production During Arteriovenous Fistula Maturation. Arterioscler Thromb Vasc Biol 37:1147-1156|
|Sadaghianloo, Nirvana; Yamamoto, Kota; Bai, Hualong et al. (2017) Increased Oxidative Stress and Hypoxia Inducible Factor-1 Expression during Arteriovenous Fistula Maturation. Ann Vasc Surg 41:225-234|
|Jablonska, Beata; Gierdalski, Marcin; Chew, Li-Jin et al. (2016) Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury. Nat Commun 7:13866|
|Salmaso, Natalina; Dominguez, Moises; Kravitz, Jacob et al. (2015) Contribution of maternal oxygenic state to the effects of chronic postnatal hypoxia on mouse body and brain development. Neurosci Lett 604:12-7|
|Koch, Marco; Varela, Luis; Kim, Jae Geun et al. (2015) Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519:45-50|
|Dimou, L; Gallo, V (2015) NG2-glia and their functions in the central nervous system. Glia 63:1429-51|
|Zonouzi, Marzieh; Scafidi, Joseph; Li, Peijun et al. (2015) GABAergic regulation of cerebellar NG2 cell development is altered in perinatal white matter injury. Nat Neurosci 18:674-82|
|Hall, Michael R; Yamamoto, Kota; Protack, Clinton D et al. (2015) Temporal regulation of venous extracellular matrix components during arteriovenous fistula maturation. J Vasc Access 16:93-106|
|Dietrich, Marcelo O; Zimmer, Marcelo R; Bober, Jeremy et al. (2015) Hypothalamic Agrp neurons drive stereotypic behaviors beyond feeding. Cell 160:1222-32|
|Agematsu, Kota; Korotcova, Ludmila; Scafidi, Joseph et al. (2014) Effects of preoperative hypoxia on white matter injury associated with cardiopulmonary bypass in a rodent hypoxic and brain slice model. Pediatr Res 75:618-25|
Showing the most recent 10 out of 32 publications