Although stroke occurs mainly in the aged population, most animal studies investigating both stroke and neurogenesis are conducted on young-adult brains. Hence, better understanding of how neural stem/progenitor cells (NSCs) are regulated after stroke in the aged brain seems essential. In the past funding period, we study the roles of aging in neurogenesis after stroke. The goal of our research in the next funding period is to focus on the mechanisms underlying regulation of stroke-induced neurogenesis by aging. Specifically, we will explore the role of the Notch pathway in neurogenesis during aging. Previous studies show that Notch signaling pathway plays critical roles during maintenance, proliferation, and differentiation of NSCs in developing brain. Recent evidence shows that Notch1 signaling is conserved in the regulation of adult neurogenesis. Our pilot studies show that Notch1 and its downstream targets are expressed in SVZ cells, and that the number of BrdU-positive (proliferating) cells in the normal adult SVZ is significantly altered after inhibiting or activating the Notch1 pathway. In addition, we find that Notch1 signaling in the SVZ is activated after stroke and that stroke-induced cell proliferation in the SVZ can be blocked by inhibiting the Notch1 pathway in young-adult brain. These results led to our hypothesis that Notch1 signaling is essential for neurogenesis to occur in the adult brain and that changes in Notch1 signaling activity may contribute, directly or indirectly, to the aged-dependent decline in neurogenesis, including that following stroke. To test this hypothesis, we propose to: (1) to examine the temporal profiles of Notch1 signaling molecule expression in the SVZ in response to aging, and to characterize the phenotypes of SVZ cells expressing Notch1 pathway molecules in the young-adult vs. aged rat brain;(2) to investigate the effect of altering the Notch1 pathway on cell proliferation and other signaling pathways in the SVZ of young-adult and aged rat brain in vivo;(3) to examine Notch1 pathway activity in the SVZ of the young-adult and aged rat brain after stroke;(4) to assess the effect of forced activation or blockade of the Notch1 pathway on neurogenesis in SVZ of young-adult and aged rat brain after stroke in vivo. The long-term goal of the proposed experiments is, by studying the mechanisms that regulate stroke- induced neurogenesis in aged brain, to achieve better understanding of the fundamental principles that govern neurogenesis in normal aging and age-related neurological diseases like stroke.

Public Health Relevance

The proposed experiments is, by studying the mechanisms that regulate stroke-induced neurogenesis in aged brain, to achieve better understanding of the fundamental principles that govern neurogenesis in normal aging and age-related neurological diseases like stroke. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
7R01AG021980-08
Application #
8287582
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Wise, Bradley C
Project Start
2003-06-01
Project End
2015-04-30
Budget Start
2012-07-15
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$285,717
Indirect Cost
$88,671
Name
University of North Texas
Department
Pharmacology
Type
Other Domestic Higher Education
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Zhang, Lin-Yuan; Lin, Pan; Pan, Jiaji et al. (2018) CLARITY for High-resolution Imaging and Quantification of Vasculature in the Whole Mouse Brain. Aging Dis 9:262-272
Zhang, Yu; Zhang, Hongxia; Lin, Siyang et al. (2018) SDF-1/CXCR7 Chemokine Signaling is Induced in the Peri-Infarct Regions in Patients with Ischemic Stroke. Aging Dis 9:287-295
Su, Qiaoer; Cheng, Yifan; Jin, Kunlin et al. (2016) Estrogen therapy increases BDNF expression and improves post-stroke depression in ovariectomy-treated rats. Exp Ther Med 12:1843-1848
Cai, Bin; Li, Wenjun; Mao, XiaoOu et al. (2016) Neuroglobin Overexpression Inhibits AMPK Signaling and Promotes Cell Anabolism. Mol Neurobiol 53:1254-65
Xie, Luokun; Choudhury, Gourav Roy; Winters, Ali et al. (2015) Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10. Eur J Immunol 45:180-91
Wang, Brian; Jin, Kunlin (2015) Current perspectives on the link between neuroinflammation and neurogenesis. Metab Brain Dis 30:355-65
Zhang, Hongxia; Shao, Bei; Zhuge, Qichuan et al. (2015) Cross-talk between human neural stem/progenitor cells and peripheral blood mononuclear cells in an allogeneic co-culture model. PLoS One 10:e0117432
Ruan, Linhui; Wang, Brian; ZhuGe, Qichuan et al. (2015) Coupling of neurogenesis and angiogenesis after ischemic stroke. Brain Res 1623:166-73
Huang, Lijie; Wu, Zhe-Bao; Zhuge, Qichuan et al. (2014) Glial scar formation occurs in the human brain after ischemic stroke. Int J Med Sci 11:344-8
Sun, Yong-Xin; Ji, Xunming; Mao, Xiaoou et al. (2014) Differential activation of mTOR complex 1 signaling in human brain with mild to severe Alzheimer's disease. J Alzheimers Dis 38:437-44

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