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Professor & Research

  • Professor & Research
  • Research activities(Type)

Research activities(Type)

Young Jae Lee, PhD

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Research Outline

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    The goals of Laboratory of Developmental Genetics are understanding pathogenic mechanisms and developing therapeutic methods of genetic disease using mice as an animal model

    1) Role of ALK1 signaling in vascular disease and tumor angiogenesis
    2) Role of Pinin in cardiovascular development
    3) Role of Sepiapterin-Reductase in tetrahydrobiopterin-associated metabolic disease
Research Contents

  • Role of ALK1 signaling in vascular disease and tumor angiogenesis 

    Vast efforts have been put into the development of drugs which can prevent or promote angiogenesis, a process of forming new blood vessels from preexisting vessels. Vascular endothelial growth factor (VEGF) and Angiopoietin have been the major focus in this area. In addition to these, much endeavor has continued to funnel into identifying novel anti-angiogenic compounds either from natural products or synthesized chemical compounds. In contrast, only little attention has been given to ALK1, which has shown to play a pivotal role in development, maintenance, and remodeling of blood vessels. ALK1 is a serine/threonine plasma membrane receptor for transforming growth factor-β (TGF-β) superfamily ligands and highly expressed in endothelial cells (ECs), predominantly in arterial (over venous) ECs during embryonic and postnatal development. Alk1-knockout mice die at midgestation, exhibiting severe vascular abnormalities characterized by excessive fusion of capillary plexus into cavernous vessels and hyperdilation of large vessels. Heterozygous ALK1 mutations cause hereditary hemorrhagic telangiectasia (HHT) (also known as Rendu-Osler-Weber syndrome), a vascular disorder characterized by nosebleeds, mucocutaneous telangiectases, and arteriovenous malformations (AVMs). Blood vessels in HHT lesions exhibit dilation of vascular lumen, thin vascular wall, and direct shunting from arteries to veins without capillaries. HHT is an autosomal-dominant vascular disorder that affects more than 1 in 10,000 individuals. Since HHT develops in individuals with suppressed ALK1 signaling, neointimal/medial hypertrophy may develop when ALK1 signaling is (over)active. Development of activators or inhibitors of ALK1 signaling would therefore serve as novel therapeutic reagents for a number of pathological conditions.


    Angiogenesis research is a cutting edge field in cancer research, due to its enormous potential for treating solid tumors regardless of their origin. As a result of 20 years of active pursuit, Avastin, a monoclonal antibody against VEGF, is now approved by FDA as a first tumor angiogenic therapy. Alk1 expression is mostly repressed in adult systemic vessels except in the lung, but is induced in the arteries and capillaries feeding to wounds or tumors. Therefore, it would be an attractive target of angiogenesis therapy for tumors.

    To investigate role of ALK1 signaling in vascular disease and tumor angiogenesis we are using following animal models.

    •Alk1-conditional knockout mice
    We generated Alk1-conditional knockout mice to inactivate Alk1 gene in tissue specific manner. Alk1-conditional allele has two loxP sequences flanking Alk1 exon3-6 region (Figure 1A), which can be deleted by tissue-specific Cre recombinase.

    • Alk1-eGFPCre transgenic mice and Alk1-eGFPCre knock-in mice
    The 9.2-kb Alk1 regulatory fragment contains the regulatory elements specific for arterial endothelial cells. We generated transgenic mouse lines, which express Cre recombinase and GFP reporter fusion protein under the control of the 9.2-kb Alk1 regulatory fragment (Figure 1B,D). We also have an Alk1-knock-in strain, whose Alk1 exons (exon3-6) are replaced with Cre recombinase and GFP reporter fusion gene (Figure 1C).

    • Rosa26-CreER transgenic mice (Jackson Laboratory)
    Rosa26 gene, which is expressed in all mouse tissues, is replaced with tamoxifen-inducible CreER gene in the transgenic mice. CreER recombinase can inactivate Alk1 gene only in tamoxifen-treated tissues.

     

    Role of Pinin in cardiovascular development

    Congenital heart defects occur in about 1% of all live births, which are the most common birth defect and a major cause of neonatal death. A large portion of congenital heart defects is related to the abnormal development of neural crest cells (NCCs) which are migrating cells originated from the dorsal neural tube of an embryo. Aberration of signal transduction pathways (i.e. Wnt, BMP, FGF pathways) in NCCs and/or adjacent tissues also causes cardiovascular malformations.

    In vitro studies showed that Pnn is involved in cell adhesion, mRNA processing, tumor suppression, and transcription regulation.  -knockout (KO) mice exhibit various developmental defects including heart outflow tract defects, cleft palate, axial vertebral transformation, and anterior eye segment dysgenesis, all of which are observed in mutant mice with developmental defects in NCC. The canonical Wnt activities are perturbed in the mutant mice. To understand the role of Pinin in cardiovascular development we are studying  -conditional knockout mice whose   gene is disrupted in NCCs using Wnt1-Cre transgenic mice.

     

    Role of Sepiapterin-Reductase in tetrahydrobiopterin-associated metabolic disease

    Tetrahydrobiopterin (BH4) is an essential cofactor for several enzymes, including all three forms of nitric oxide synthases, three aromatic hydroxylases, and glyceryl-ether mono-oxygenase. A proper level of BH4 is, therefore, necessary for the metabolism of phenylalanine and the production of nitric oxide, catecholamines, and serotonin. BH4 deficiency has been shown to be closely associated with diverse neurological psychiatric disorders. Sepiapterin reductase (SPR) is an enzyme that catalyzes the final step of BH4 biosynthesis. Mice deficient in the Spr gene (Spr-/-) exhibit phenylketonuria, dwarfism, and impaired body movement. The biochemical and behavioral characteristics of Spr-/- mice share striking similarities with the symptoms observed in SPR-deficient patients. The Spr-/- mice and Spr-conditional knockout mice, which we are generating, will be invaluable resources to elucidate many important issues regarding SPR and BH4 deficiencies.



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    The goals of Laboratory of Developmental Genetics are understanding pathogenic mechanisms and developing therapeutic methods of genetic disease using mice as an animal model
     
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