PTHrP (parathyroid hormone-related protein) was originally identified as the tumor product responsible for the clinical syndrome of humoral hypercalcemia of malignancy. It is now clear that PTHrP is a normal product of many tissues including the lung, where it appears to act in a paracrine fashion to regulate organogenesis. PTHrP is a normal product of lung epithelial cells, and recent experiments in our laboratory have demonstrated that targeted overexpression of PTHrP in the murine type II alveolar cells of the lung leads to abnormal lung development during embryonic life. Branching morphogenesis appears to undergo local arrest at the transition from the respiratory bronchiole to the alveolar duct resulting in an unbranched pocket or cyst. A similar stage-specific defect in pulmonary differentiation and branching is also seen in the human disease, congenital cystic adenomatoid malformation which typically results in fatal respiratory distress in infants. To test our hypothesis of a stage-specific arrest in pulmonary branching induced by PTHrP, our objective is to examine the timing of the biological responsiveness to PTHrP, the effects of PTHrP on the programs of cellular differentiation and apoptotic cell death in the lung and the integration of PTHrP signaling into the network of factors known to control lung development. Finally, we will characterize the differential gene expression in embryonic lung from normal and SPC-PTHrP overexpressors at peak phenotype to define the molecular mechanisms by which PTHrP regulates embryonic lung gland development. The identification of the components involved in the PTHrP signaling pathway and the elucidation of the mechanism of their action offers the potential for manipulating this process and perhaps compensating for the above described developmental defects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL010281-02
Application #
6182826
Study Section
Special Emphasis Panel (ZRG1-RAP (01))
Project Start
2000-07-01
Project End
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
2
Fiscal Year
2000
Total Cost
$42,628
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520