ABSTRACT The goal of this pilot project is to study lung disease in Osteogenesis imperfecta (OI) and to explore if recessive forms of OI cause defective post-translational modification (PTM) of surfactant proteins and negatively impact lung function. OI is a connective tissue disease that causes severely reduced bone mass and high fracture rate and is most commonly caused by dominant mutations in type I collagen genes, COL1A1 and COL1A2. Because type I collagen is present in most tissues, the disease is systemic and a significant issue in patients with moderate to severe OI is poor respiratory function and increased susceptibility to lung infections which can lead to fatal pneumonia. Respiratory distress can also be present at birth and have a poor prognosis. Although impaired respiratory function in growing patients can be secondary to skeletal deformities such as scoliosis, a decline in pulmonary function tests is also observed in moderate forms of the disease with absence of scoliosis. How collagen defects causing OI negatively impact lung function is not understood and poorly studied. In Specific Aim 1 we propose the hypothesis that OI-causing alterations in type I collagen lead to a congenital primary lung defect. We will perform histological, morphometric, apoptosis, cell proliferation and electron microscopy studies in three different mouse models of OI to identify the underlying morphological and cellular defects. In Specific Aim 2 we will pursue the innovative hypothesis that surfactant protein D and A are post- translationally modified by the same prolyl 3-hydroxylation complex that modifies type I collagen and whose mutations cause recessive forms of OI. We will show that the components of the prolyl 3-hydroxylation complex are also expressed in type II alveolar cells and that the loss of function of the prolyl 3-hydroxylation complex also causes defective PTM of surfactant protein D and A, using mass-spectrometry. Our preliminary data clearly point at a primary defect in the lung of mouse models of OI and this proposal will begin to elucidate this poorly studied aspect of OI and lay the foundation for future, larger studies on the role of collagen and ECM in lung development.