Visceral sensory pathways that innervate the cardiovascular, respiratory and gastrointestinal systems are critical for reflex control of autonomic homeostasis. It is well established that functional characteristics of visceral reflexes, including arterial baro- and chemoreflexes, changes dramatically during perinatal development. However, the cellular mechanisms underlying the functional maturation of visceral reflexes are largely unknown. The leading hypothesis of this proposal is that the neurotrophin Brain-Derived Neurotrophic Factor (BDNF), released from the central terminals of visceral sensory afferents, regulates the activity-dependent maturation of postsynaptic target neurons. This hypothesis, supported by our recently published data and preliminary studies, will be tested using nodose ganglion primary and second-order sensory neurons, as well as functionally homogenous primary and second-order neurons in the aortic baroreceptor pathway, as a model. The proposed studies will utilize several innovative techniques, uniquely suited for studies of this kind, to characterize: 1) developmental regulation of activity-dependent expression of BDNF in nodose ganglion primary sensory neurons in general, and baroreceptor afferents in particular, and 2) electrophysiological and morphological effects of BDNF on second-order sensory neurons, including baroreceptor-relay neurons, from the developing nucleus tractus solitarius (NTS). A novel combination of electrical field stimulation with a highly sensitive, modified ELISA in situ, will be used to characterize changes in BDNF protein content in response to patterns of stimulation that mimic the physiological activity of baroreceptor afferents. Revealing the cellular mechanisms of BDNF regulation in visceral primary sensory neurons is a key to understanding BDNF role in visceral sensory pathways. A second part of the proposed work will analyze BDNF effects on voltage-activated potassium currents and dendritic morphology in specifically identified postsynaptic targets of BDNF-containing visceral sensory neurons and baroreceptor afferents. Results of these studies will provide new information fundamental to our understanding of basic mechanisms that govern development of sensory pathways. Moreover, by using the arterial baroreceptor pathway as a model, the proposed studies are relevant to understanding pathogenesis of developmental disorders of the cardio-respiratory system, such as Sudden Infant Death Syndrome (SIDS). ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076113-04
Application #
7324838
Study Section
Special Emphasis Panel (ZRG1-CICS (01))
Program Officer
Thrasher, Terry N
Project Start
2004-12-05
Project End
2009-11-30
Budget Start
2007-12-15
Budget End
2008-11-30
Support Year
4
Fiscal Year
2008
Total Cost
$249,320
Indirect Cost
Name
Oregon Health and Science University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Morrow, Jarrett D; Cho, Michael H; Platig, John et al. (2018) Ensemble genomic analysis in human lung tissue identifies novel genes for chronic obstructive pulmonary disease. Hum Genomics 12:1
Sakornsakolpat, Phuwanat; Morrow, Jarrett D; Castaldi, Peter J et al. (2018) Integrative genomics identifies new genes associated with severe COPD and emphysema. Respir Res 19:46
Morrow, Jarrett D; Glass, Kimberly; Cho, Michael H et al. (2018) Human Lung DNA Methylation Quantitative Trait Loci Colocalize with Chronic Obstructive Pulmonary Disease Genome-Wide Association Loci. Am J Respir Crit Care Med 197:1275-1284
Sharma, Amitabh; Kitsak, Maksim; Cho, Michael H et al. (2018) Integration of Molecular Interactome and Targeted Interaction Analysis to Identify a COPD Disease Network Module. Sci Rep 8:14439
Radder, Josiah E; Gregory, Alyssa D; Leme, Adriana S et al. (2017) Variable Susceptibility to Cigarette Smoke-Induced Emphysema in 34 Inbred Strains of Mice Implicates Abi3bp in Emphysema Susceptibility. Am J Respir Cell Mol Biol 57:367-375
Busch, Robert; Hobbs, Brian D; Zhou, Jin et al. (2017) Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects. Am J Respir Cell Mol Biol 57:35-46
Morrow, Jarrett D; Zhou, Xiaobo; Lao, Taotao et al. (2017) Functional interactors of three genome-wide association study genes are differentially expressed in severe chronic obstructive pulmonary disease lung tissue. Sci Rep 7:44232
Kaplan, Robert M; Sun, Qiankun; Ries, Andrew L (2015) Quality of well-being outcomes in the National Emphysema Treatment Trial. Chest 147:377-387
Dodd, James W; Novotny, Paul; Sciurba, Frank C et al. (2015) Executive Function, Survival, and Hospitalization in Chronic Obstructive Pulmonary Disease. A Longitudinal Analysis of the National Emphysema Treatment Trial (NETT). Ann Am Thorac Soc 12:1473-81
Vermehren-Schmaedick, A; Khanjian, R A; Balkowiec, A (2015) Cellular mechanisms of activity-dependent BDNF expression in primary sensory neurons. Neuroscience 310:665-73

Showing the most recent 10 out of 41 publications