The candidate, Donna L. Cioffi, is a first-year postdoctoral fellow in the laboratory of Dr. Troy Stevens at the University of South Alabama (USA). The candidate's immediate career goals include two additional years at USA, as a postdoc, performing the first phase of the proposed project. Long-term career goals include a tenure-track position at a university. Although the candidate's husband is a tenured faculty member at USA, she is not limiting her search to just USA. The candidate and her husband are willing to relocate to a new university should an opportunity arise for both. During the mentored phase of the project the candidate will be trained in patch clamp electrophysiology and basic molecular biology techniques. These techniques will be used throughout the mentored and independent phases of the proposed project in addition to future studies. This research project focuses on endothelial barrier disruption, a contributing factor to the development and progression of pathophysiological states including inflammation, atherosclerosis and acute respiratory distress syndrome. The endothelial Isoc channel is a calcium selective ion channel whose activation is an important step leading to the formation of inter-endothelial cell gaps and endothelial barrier disruption. Isoc activation/inactivation properties largely determine the amount of calcium which enters the cell and as such, influence the magnitude and dynamics of gap formation. A protein 4.1 binding domain together with an adjacent proline-rich region located on the TRPC4 subunit of the Isoc channel are important for channel activation. In the mentored phase of this project, the independent roles of the protein 4.1 binding domain and proline-rich region in channel activation or inactivation will be determined. Further, while it is known that Isoc inactivation is both calcium- and phosphorylation-dependent, it is unknown whether these pathways are part of a common mechanism. The independent phase of this project will determine whether a common calcium/phosphate pathway underlies inactivation of the Isoc channel.

Public Health Relevance

Endothelial cells line the inside of blood vessels forming an endothelial barrier. Endothelial barrier disruption contributes to the development and progression of mutiple diseases, including cardiovascular and lung diseases. This project will study mechanisms of endothelial barrier disruption.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL089361-04
Application #
8127803
Study Section
Special Emphasis Panel (NSS)
Program Officer
Gao, Yunling
Project Start
2009-09-15
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$248,999
Indirect Cost
Name
University of South Alabama
Department
Biology
Type
Schools of Medicine
DUNS #
172750234
City
Mobile
State
AL
Country
United States
Zip Code
36688
Kadeba, Pierre I; Vasauskas, Audrey A; Chen, Hairu et al. (2013) Regulation of store-operated calcium entry by FK506-binding immunophilins. Cell Calcium 53:275-85
Cioffi, Donna L; Wu, Songwei; Chen, Hairu et al. (2012) Orai1 determines calcium selectivity of an endogenous TRPC heterotetramer channel. Circ Res 110:1435-44
Cioffi, Donna L; Pandey, Subha; Alvarez, Diego F et al. (2012) Terminal sialic acids are an important determinant of pulmonary endothelial barrier integrity. Am J Physiol Lung Cell Mol Physiol 302:L1067-77
Cioffi, Donna L (2011) Redox regulation of endothelial canonical transient receptor potential channels. Antioxid Redox Signal 15:1567-82
Cioffi, Donna L; Hubler, Tina R; Scammell, Jonathan G (2011) Organization and function of the FKBP52 and FKBP51 genes. Curr Opin Pharmacol 11:308-13