Developmental Biology

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Principal Investigator:  David Warburton, DSc, MD, FRCP

Emerging Initiative
The Developmental Biology program brings clinical surgery together with basic research.  Kasper S. Wang, MD, a surgeon in the Division of General Pediatric Surgery at Childrens Hospital Los Angeles, and Saverio Bellusci, PhD, an investigator in The Saban Research Institute are working together to explore the mysterious ways in which a natural protein called Fibroblast Growth Factor 10 (FGF 10) acts on the liver.

As a pediatric surgeon, Dr. Wang needs his patients to have a healthy liver because without it, their blood can’t clot, toxins accumulate and essential proteins dissipate. The team’s initial laboratory studies indicate that FGF 10 activates the organ’s ordinarily dormant progenitor cells—relatively
immature cells that promote cell proliferation crucial to tissue repair after surgery or injury.

What This Means

Hemophilia Example
For children with hemophilia, it might be possible to import healthy versions of the defective gene that causes their disorder

Liver Cancer Example
In liver cancer, when so much healthy and diseased organ has to be removed that young lives sometimes are jeopardized, short-term treatment with a synthetic FGF 10 agent might possibly encourage better, faster regeneration of normal liver tissue.

Research Focus

The Developmental Biology Program seeks to discover the basic mechanisms of human organ development, repair and regeneration. Recent advances in Developmental Biology hold great promise in many areas of human adult and child health, where organ regeneration, stem cell based therapy or tissue engineering could be life saving. 

At our hospital, therapeutic targets for eventual translation to the bedside include lung hypoplasia or injury caused by prematurity, cleft palate, abnormal skin wounds, short gut and diabetes. The Program looks forward to exploiting the new scientific opportunities arising from analysis of the function of the completed human genome in child development and disease, as well as beginning new initiatives in tissue engineering of the genitourinary system.

The Developmental Biology Program is organized into organ-based sections that carry out scientific inquiries within the overall program focus of Organogenesis, Injury, Repair, Tissue Regeneration and Engineering.  Organs of current focus are the lungs, the palate, the pancreas, the skin, the gut, and the mammary glands.

Scientific inquiries related to these organs include:

• Organogenesis: understanding the molecular and genetic basis of organogenesis of selected organ systems, currently including the breast, gut, lung, palate, pancreas and skin.
• Injury: understanding the impact of adverse events such as premature delivery, infection, inflammation, hyperoxia or hypoxia on successful organogenesis.
• Inflammation: understanding the role of inflammatory peptides and cytokines in initiating and maintaining lung inflammation.
• Repair: understanding the molecular and genetic basis of normal and abnormal organ repair, including such processes as organ based stem cell activation, fetal wound healing, scarring and fibrosis.
• Regeneration: exploring the molecular and genetic basis for stem cell based organ regeneration as a rational basis for eventual novel approaches to cell based organ regeneration therapy.
• Tissue engineering: to discover novel methods of tissue reconstruction, based upon scientific principles derived from understanding of organ development.
• Malignant Transformation: to understand certain forms of cancer as developmental aberrations and to devise low toxicity therapies for lung and breast cancer based on understanding normal organ development.

Accomplishments

Lung Morphogenesis, Injury, Repair, Regeneration
Several new discoveries were made in this field:

1. A new role for protein ectodomain sheddases in lung morphogenesis and vasculogenesis  has been identified (Zhao et al, 2001a,b). 
2. New insights into the role of Smad and non-Smad signaling in lung fibrosis have been reported (Zhao et al, 2002).
3. New signaling mechanisms in inflammation (Phagoo et al, 2001)
4. New mechanisms in lung cell signal transduction have been discovered (Flores-Delgado et al, 2001, Shi et al, 2001, Mailleux et al, 2001, Shi et al, 2001).
5. New insights into lung repair processes (Buckley et al, 2001) and into mechanisms of lung hypoplasia and regeneration (Acosta et al, 2001a,b) have been obtained.

Molecular Basis of Palatal Fusion
The role of the RhoA and Rho kinase pathway in palatal fusion was defined (Kaartinen et al, 2002) and several new roles of Rac GTP ases in palatal development were discovered (Kaartinen et al, 2002, 2001, Haataja et al, 2002).Clefting in TGF-ß3 null mice results from failure of trans-differentiation of medial edge epithelium and Assoc.d degradation of medial edge epithelial basement membrane. It was also discovered that TGF-ß3 induced palatal fusion requires metalloproteinases (Blavier et al, 2001).A novel method for removing floxed genes from conditional knockouts was also discovered (Kaartinen and Nagy, 2001).

Pancreatic Morphogenesis
A novel role for FGF10 was found in maintaining the proliferative capacity of progenitor cells during pancreatic morphogenesis (Bhushan et al, 2001).

Scarless Repair and Metalloprotease Activation Mechanisms in Human Skin
Two novel mechanisms were discovered by which exogenous growth factors and cytokines can activate metalloproteases (Han et al, 2002, 2001).
A correlation was discovered between PAI-1 expression and scarring was demonstrated using in a novel utero fetal skin wounding model (Huang et al, 2002).

Molecular Basis of Mammary Gland Morphogenesis
A critical role for FGF signaling was discovered in early breast morphogenesis (Mailleux et al, 2002).

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