Premature infants suffer a high rate of long-term pulmonary complications. In the womb, the fetal lung is exposed to mechanical forces that are critical for normal lung development. Our laboratory is trying to understand how the fetal lungs respond to these physical forces. We have identified several proteins that are activated by stretch. We hope the information derived from our studies will uncover a way to accelerate lung development to help babies born prematurely.

Institutions

Wih

Research Description

Normal lung growth and development during fetal life are critical for extrauterine survival. Premature infants are often born before sufficient lung maturation has occurred, and as a result, they experience a high rate of long-term pulmonary complications, such as bronchopulmonary dysplasia. In addition, inadequate lung growth for gestational age (pulmonary hypoplasia) is found in ~25% of neonatal autopsies. These developmental lung disorders are a major source of infant morbidity and mortality. Understanding the mechanisms of perinatal lung growth and development is a crucial step for design of preventive and therapeutic strategies.

Mechanical forces generated in utero by repetitive breathing movements and by fluid distension are essential to mammalian lung development. However, the mechanisms by which pulmonary cells sense and transduce mechanical signals are largely unknown.

A key component of lung development is the differentiation of the alveolar type II epithelial cells, the major source of pulmonary surfactant that prevents alveolar collapse during expiration. Using an in vitro system, previous studies from our laboratory found that mechanical strain induces fetal type II cell maturation. This process is mediated via the extracellular-regulated protein kinase (ERK) and the cAMP-PKA-dependent signaling pathways. In addition, we have identified potential roles for the epidermal growth factor receptor (EGFR) and specific integrin subtypes in mechanotransduction during alveolar development. Current efforts are directed to understand how different receptors cross-talk to promote lung differentiation.

The identification of key regulatory pathways regulating fetal type II cell differentiation may facilitate development of new approaches to accelerate lung maturation in clinical conditions where lung development is impaired.

Awards

1998 "Effects of Mechanical Forces on Pulmonary Epithelial Gene Expression
and Differentiation". Selected for news media coverage. Annual meeting of
the Pediatric Academic Societies (APS/SPR/APA), New Orleans, LA.

1998 "Mechanical Forces Regulate Surfactant Protein Gene Expression
in Isolated Alveolar Epithelial Cells and Type II Cell Phenotype". Young
Investigator's Award on Basic Science. 6th Annual Hospital Research
Celebration, Posters Session. Rhode Island Hospital, Providence, RI.

2001 Selected to participate in the new mentoring program for
Beginning Faculty, Brown Medical School.

2003 Richard B. Salomon Faculty Award (Brown Medical School)

2004 Parker B. Francis Fellow

2005-present Committee Member, New England Perinatal Society

Affiliations

1988-1994 Catalan Society of Neonatology, Barcelona, Spain

1995-present American Academy of Pediatrics

1997-present New England Perinatal Society

1998-present Eastern Society for Pediatric Research

2000-present American Thoracic Society

2001-present American Physiological Society

2001-present The American Society for Cell Biology

2003-present Society for Pediatric Research

Funded Research

GRANTS

1. Spanish training research grant
   Project period: 1984-1988


2. "Mechanotransduction and Lung Alveolar Differentiation"
   Principal Investigator: Juan Sanchez-Esteban, M.D.
   Agency: The Rhode Island Foundation
   Project period: 01/01/2003 to 12/31/2003
   Amount: $7,000


3. "Mechanotransduction and Lung Alveolar Differentiation"
   Principal Investigator: Juan Sanchez-Esteban, M.D.
   Agency: Brown Medical School
   Project period: 01/03/2003 to 02/28/2004
   Amount: $14,750


4. "Mechanotransduction and Lung Alveolar Differentiation"
   Principal Investigator Project III: Juan Sanchez-Esteban, M.D.
   Agency: NIH (1 P20 RR018728-01 COBRE in Perinatal Biology)
   Project period: 10/01/2003 to 9/30/2008
   Amount: $745,990


5. "Mechanotransduction and Lung Alveolar Differentiation"
   Principal Investigator: Juan Sanchez-Esteban, M.D.
   Agency: Parker B. Francis Fellowship Program
   Project period: 07/2004 to 06/2007
   Amount: $126,000

1. NIH Minority Short Term Training Grant (NHLBI)
   Role: Faculty Mentor (PI: S. Rounds, M.D.)
   Term: 2004-present


2. NIH Training Grant for Perinatal Biology
   Role: Mentor (PI: J.F. Padbury)
   Term: 2004-2005

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