One main consequence of numerous cardiovascular, neurologic and respiratory disorders, whether in the neonate, older infant or at a later more mature age, is tissue O2 deprivation. Clinically, such a consequence can have devastating effects, especially on susceptible organs such as the brain, heart and kidney. Besides the type of organ, there are a number of factors that can determine the response of tissue to hypoxia. It has been well demonstrated that the developing mammal responds differently to hypoxia than the mature subject, both in vivo and in-vitro. Our overall Program hypothesis is that O2 deprivation leads to alterations in cytosolic, membrane and nuclear events that form the underlying basis for cellular adaptation, sublethal injury or cell death. The extent of these alterations depends on many factors including age, type cell and its endowments in both excitable (e.g. neurons and cardiac myocytes) and nonexcitable cells (e.g. glia, renal tubular epithelium), and severity and chronicity of hypoxia. The central aims of this Program will therefore be to 1) to define the nature of the responses to hypoxia in mature and immature neurons, glia, cardiac myocytes and epithelia and 2) to identify the mechanisms underlying these developmental changes at the cellular and molecular levels using a variety of approaches and techniques. To address these aims and determine the mechanisms that can lead to injury or adaptation and survival in the mature and immature cell, we are submitting a revised competing renewal of our Program Project. This program is based on 4 major projects that are interactive, interdependent and that share facilities (4 Cores), concepts and experimental approaches. To accomplish these aims, we use state-of-the art techniques and methodologies including eletrophysiologic methods, electron, confocal and video-microscopy, molecular biologic and genetic techniques to study native tissue, dissociated and cultured cells. The studies outlined in this Program represent a natural extension of work currently done by each PI in the Program. We firmly believe that this Program will provide the opportunity of enhancing the productivity of each individual project and, perhaps more importantly, the synthesis of new concepts about susceptibility or tolerance to anoxia and the formulation of therapeutic modalities.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD032573-14
Application #
7479729
Study Section
Special Emphasis Panel (ZHD1-MCHG-B (HG))
Program Officer
Willinger, Marian
Project Start
1996-12-01
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
14
Fiscal Year
2008
Total Cost
$1,211,152
Indirect Cost
Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Yao, Hang; Azad, Priti; Zhao, Huiwen W et al. (2016) The Na+/HCO3- co-transporter is protective during ischemia in astrocytes. Neuroscience 339:329-337
Jha, Aashish R; Zhou, Dan; Brown, Christopher D et al. (2016) Shared Genetic Signals of Hypoxia Adaptation in Drosophila and in High-Altitude Human Populations. Mol Biol Evol 33:501-17
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Gu, Xiang Q; Pamenter, Matthew E; Siemen, Detlef et al. (2014) Mitochondrial but not plasmalemmal BK channels are hypoxia-sensitive in human glioma. Glia 62:504-13
Gersten, Merril; Zhou, Dan; Azad, Priti et al. (2014) Wnt pathway activation increases hypoxia tolerance during development. PLoS One 9:e103292
Udpa, Nitin; Ronen, Roy; Zhou, Dan et al. (2014) Whole genome sequencing of Ethiopian highlanders reveals conserved hypoxia tolerance genes. Genome Biol 15:R36
Salameh, Ahlam Ibrahim; Ruffin, Vernon A; Boron, Walter F (2014) Effects of metabolic acidosis on intracellular pH responses in multiple cell types. Am J Physiol Regul Integr Comp Physiol 307:R1413-27
Douglas, Robert M; Chen, Alice H; Iniguez, Alejandra et al. (2013) Chemokine receptor-like 2 is involved in ischemic brain injury. J Exp Stroke Transl Med 6:1-6
Parker, Mark D; Boron, Walter F (2013) The divergence, actions, roles, and relatives of sodium-coupled bicarbonate transporters. Physiol Rev 93:803-959

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