My long-term goal is to elucidate mechanisms for glial development. The focus of this application is to characterize local proliferation of astrocytes in the cerebral cortex and the mechanism underlying their interaction with blood vessels at the postnatal stage. During postnatal weeks 2 and 3, the density of blood vessels and the number of glial cells both increase by ~4 fold in the rodent brain. It is still unclear where the large number of astrocytes come from and how they interact with blood vessels. My preliminary data show that postnatal local proliferation of astrocytes is widely distributed in different layers of the cerebral cortex, and these astrocytes retain their endfeet (perivascular processes of astrocytes) with blood vessels while they enter mitotic stages. I thus hypothesize that local prolifaration of astrocytes is a main source of cortical astrocytes that contribute to endfoot formation in the postnatal brain. To address the hypothesis, I propose two specific aims: (1) Characterize local proliferation of astrocytes and their fate and function in the cerebral cortex; (2) Elucidate the mechanism underlying endfoot formation around blood vessels mediated by locally generated astrocytes. I have established two groups of transgenic mouse lines to sparsely label astrocytes via genetically encoded fluorescent markers with unprecedented resolution, along with methods I developed to label and record dividing cells. I am therefore uniquely poised to undertake this novel study. Research proposed in the K99 Mentored phase (year 1 and 2) is concentrated on the establishment of methods for retroviral labeling and imaging of glial proliferation in live animals, which will be carried out with the supervision of Dr. Lily Jan. The R00 Independent phase (years 3 to 5) will focus on characterizing the function of astrocytes generated via local proliferation, and the mechanism underlying their interaction with blood vessels. The proposed research is innovative because it will provide the first direct evidence of postnatal local proliferation of astrocytes in cerebral cortex and show how they integrate into glial network and form endfoot structures with blood vessels.

Public Health Relevance

The outcomes of these experiments will greatly improve our understanding of a variety of neurological diseases such as ischemic stroke and brain tumors caused by dysfunction of glial-vascular interaction or uncontrolled glial proliferation. Elucidation of the mechanism of formation of glial-vascular interaction will further facilitate development of new therapeutic targets for the treatment of these neurological diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Transition Award (R00)
Project #
5R00NS073735-05
Application #
8996210
Study Section
Special Emphasis Panel (NSS)
Program Officer
Koenig, James I
Project Start
2013-09-05
Project End
2017-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Jia, Jie-Min; Peng, Chuanqi; Wang, Yihui et al. (2018) Control of occlusion of middle cerebral artery in perinatal and neonatal mice with magnetic force. Mol Brain 11:47
Jing, Dian; Zhang, Shiwen; Luo, Wenjing et al. (2018) Tissue clearing of both hard and soft tissue organs with the PEGASOS method. Cell Res 28:803-818
Celen, Cemre; Chuang, Jen-Chieh; Luo, Xin et al. (2017) Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment. Elife 6:
Peng, Chuanqi; Gao, Xiaofei; Xu, Jing et al. (2017) Targeting orthotopic gliomas with renal-clearable luminescent gold nanoparticles. Nano Res 10:1366-1376
Jia, Jie-Min; Chowdary, Praveen D; Gao, Xiaofei et al. (2017) Control of cerebral ischemia with magnetic nanoparticles. Nat Methods 14:160-166
Ge, W-P; Jia, J-M (2016) Local production of astrocytes in the cerebral cortex. Neuroscience 323:3-9
Shen, Yiguo; Ge, Woo-Ping; Li, Yulong et al. (2015) Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis. Proc Natl Acad Sci U S A 112:2935-41
Yu, Dan; Gustafson, William Clay; Han, Chun et al. (2014) An improved monomeric infrared fluorescent protein for neuronal and tumour brain imaging. Nat Commun 5:3626
Ge, Woo-Ping; Miyawaki, Atsushi; Gage, Fred H et al. (2012) Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484:376-80