This revised proposal describes a 5-year program for the development of the candidate's career as an independent clinician-scientist focused on lung vascular biology.,The candidate, an Assistant Professor in UCSF's Department of Surgery with research experience in the cardiopulmonary system, will perform this work with strong institutional support in an environment that includes an outstanding research program in vascular biology. I propose to study the role of Ndtch4 signaling in the development of lung arteriovenous malformations (AVMs). Mice that constitutively express endothelial Notch4 develop AVMs in extrapulmonary sites as well as hemorrhages in the lungs and filling defects on pulmonary angiograms. Common bile duct ligation induces lung AVMs in rats and impairs lung function in mice. I hypothesize that Notch4 signaling is necessary and sufficient for the development of lung AVMs.
The specific aims are: 1) To determine the effect of constitutively active endothelial Notch4 on the structure and function of the mouse lung vasculature. 2) To evaluate lung vascular remodeling after common bile duct ligation in the absence of Notch4. 3) To determine the effect of lung-AVM-patient serum on human pulmonary endothelial cells. The experiments in this proposal will use vascular casting, microcomputed tomography, and other indirect methods to rigorously characterize the lung vasculature in the context of Notch4 signaling. First, mouse lungs will be evaluated after different durations of constitutive endothelial Notch4 expression. Second, the mouse common bile duct ligation model will be further characterized and the necessity of Notch4 for lung vascular changes will be tested by performing the procedure on Notch4-/- mice.
The final aim will establish the relevance of aims 1 and 2 in the human disease process and will provide evidence for a "hepatic factor" that regulates lung vascular remodeling. Specifically, cultured human pulmonary endothelial cells will be exposed to serum from patients with documented lung AVMs, and both Notch signaling and endothelial cell behavior will be assessed. This work will determine the role of Notch4 expression in the development of lung vascular abnormalities and will begin to characterize the cellular and molecular mechanisms involved.

Public Health Relevance

Lung arteriovenous malformations are a significant clinical problem for which there is no effective medical treatment. The ultimate goal of this research is to lead to new molecular targets of therapy for patients with lung AVMs and other pulmonary vascular disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL092062-05
Application #
8516562
Study Section
Special Emphasis Panel (ZHL1-CSR-O (O1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$122,914
Indirect Cost
$9,105
Name
University of California San Francisco
Department
Surgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Shue, Eveline H; Schecter, Samuel C; Gong, Wenhui et al. (2014) Antenatal maternally-administered phosphodiesterase type 5 inhibitors normalize eNOS expression in the fetal lamb model of congenital diaphragmatic hernia. J Pediatr Surg 49:39-45; discussion 45
Shue, Eveline; Wu, Jianfeng; Schecter, Samuel et al. (2013) Aberrant pulmonary lymphatic development in the nitrofen mouse model of congenital diaphragmatic hernia. J Pediatr Surg 48:1198-204
Jelin, Eric B; Etemadi, Mozziyar; Encinas, Jose et al. (2011) Dynamic tracheal occlusion improves lung morphometrics and function in the fetal lamb model of congenital diaphragmatic hernia. J Pediatr Surg 46:1150-7
Miniati, Doug; Jelin, Eric B; Ng, Jennifer et al. (2010) Constitutively active endothelial Notch4 causes lung arteriovenous shunts in mice. Am J Physiol Lung Cell Mol Physiol 298:L169-77