This application describes a comprehensive vascular research program designed to develop Dr. Childs into an independent investigator. Through course work in molecular biology, research design, and statistics, he will acquire the necessary analytical skills to achieve this goal. He will also be required to attend several annual conferences and a monthly journal club. An Advisory Board of experienced investigators in vascular and cellular biology has been established for Dr. Childs to obtain hands on experience in laboratory techniques. Development of grantsmanship is emphasized throughout the duration of the K01 award, beginning with applications for local funds, graduating to an American Heart Association grant, and culminating in a R01 submission to the NIH in the third year of this award. The research plan focuses on the regulation of endothelial cell-cell adherens junctions to prevent microvascular hyperpermeability following hemorrhagic shock. Fluid loss from the circulation is a major factor in compromising cardiovascular homeostasis following trauma, burns, sepsis and hemorrhagic shock. Preventing microvascular barrier opening or reestablishing barrier function is crucial in limiting the deleterious effects on the cardiovascular, pulmonary and nervous systems. Hemorrhagic shock-induced hyperpermeability results in alteration of the endothelial cell-cell adherens junction complex. Site-specific alterations in the structure of (3-catenin have been implicated as an important modulator of these junctions. The applicant hypothesizes that hemorrhagic shock-induced activation of caspases results in a (3- catenin-dependent modification of endothelial adherens junction. To address this hypothesis, the applicant proposes two interlocking specific aims: (1) define the relationship between the apoptotic cascade and hemorrhagic shock-induced hyperpermeability and (2) identify the interaction(s) of caspase-3 with the adherens junction complex. Intravital microscopy with a novel in vivo protein transfection technique in parallel with cell monolayers will be utilized to determine changes in microvascular hyperpermeability. Atomic force microscopy will be used to assess endothelial cell adhesive forces.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01HL076815-05
Application #
7806477
Study Section
Special Emphasis Panel (ZHL1-CSR-B (F2))
Program Officer
Meadows, Tawanna
Project Start
2006-09-25
Project End
2011-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
5
Fiscal Year
2010
Total Cost
$136,080
Indirect Cost
Name
Scott and White Memorial Hospital
Department
Type
DUNS #
076697960
City
Temple
State
TX
Country
United States
Zip Code
76504
Tharakan, Binu; McNeal Jr, Sam I; Hunter, Felicia A et al. (2015) RECOMBINANT BCL-XL ATTENUATES VASCULAR HYPERPERMEABILITY IN A RAT MODEL OF HEMORRHAGIC SHOCK. Cell Death Discov 1:
Sawant, Devendra A; Tharakan, Binu; Hunter, Felicia A et al. (2015) Glycogen synthase kinase 3 inhibitor protects against microvascular hyperpermeability following hemorrhagic shock. J Trauma Acute Care Surg 79:609-16
Sawant, Devendra A; Tharakan, Binu; Wilson, Rickesha L et al. (2013) Regulation of tumor necrosis factor-?-induced microvascular endothelial cell hyperpermeability by recombinant B-cell lymphoma-extra large. J Surg Res 184:628-37
Sawant, Devendra A; Tharakan, Binu; Tobin, Richard P et al. (2013) Inhibition of Fas-Fas ligand interaction attenuates microvascular hyperpermeability following hemorrhagic shock. Shock 39:161-7
Childs, Ed W; Tharakan, Binu; Hunter, Felicia A et al. (2010) 17beta-estradiol mediated protection against vascular leak after hemorrhagic shock: role of estrogen receptors and apoptotic signaling. Shock 34:229-35
Childs, Ed W; Tharakan, Binu; Nurudeen, Suliat et al. (2010) Cyclosporine A--protection against microvascular hyperpermeability is calcineurin independent. Am J Surg 199:542-8
Tharakan, Binu; Whaley, J Greg; Hunter, Felicia A et al. (2010) (-)-Deprenyl inhibits vascular hyperpermeability after hemorrhagic shock. Shock 33:56-63