Hemangiomas are vascular tumors formed by uncontrolled angiogenesis. These neoplastic lesions appear approximately 2 weeks after birth, proliferate over the following year, then subsequently undergo a slow period of involution (regression). Although some breakthroughs in understanding the molecular mechanisms that induce the proliferative phase of hemangioma progression have been made, little is known about why these tumors naturally regress. Adipogenesis is a prevalent mechanism during the involuting phase, as vascular tissue is replaced by fat tissue. However, significant insights into the molecular basis of this process do not exist. Our long-term goal is to gain an understanding of the mechanisms that cause hemangioma regression. This knowledge may lead to development of novel therapies for treatment of vascular tumors and other diseases. We hypothesize that macrophage infiltration into hemangiomas induces endothelial to mesenchymal transition (EndMT), and that these endothelial-derived mesenchymal cells take on a multipotent stem cell-like phenotype and differentiate into adipocytes to mediate hemangioma involution.
The specific aims are: 1. To determine whether macrophages promote endothelial to mesenchymal transition as a mechanism of hemangioma regression. We suspect that elevated expression of MCP-1 causes recruitment of macrophages into involuting hemangiomas. We hypothesize that these macrophages secrete TGF-β2, which will induce hemangioma endothelial cells to undergo endothelial to mesenchymal transition. 2. To determine if cells formed by endothelial to mesenchymal transition acquire a stem cell phenotype and differentiate into adipocytes during hemangioma regression. We hypothesize that endothelial to mesenchymal transition forms multipotent stem-like cells in hemangiomas. We predict that cytokines such as IGF-1 are secreted from macrophages to induce differentiation of these stem-like cells into adipocytes during hemangioma involution. 3. To generate a mouse model of endothelial to mesenchymal transition. We propose to produce doxycycline inducible wild-type and mutant (constitutively active) ALK2-RFP transgenic mice that will be crossed with VE-Cadherin-Cre;Rosa26-rtTA-EGFP mice in order to selectively induce and track EndMT and subsequent cell differentiation in vivo. This will allow us to further investigate the role of EndMT in vascular regression and other physiological or pathological processes in vivo.
Hemangioma is the most common tumor effecting children, with approximately 10% of the Caucasian population developing some form of the disease. Despite the fact that most hemangiomas naturally regress over time, they can cause scarring and disfigurement of patients and many can be life threatening. Our proposed studies will help to understand the cause of hemangioma regression, which may lead to development of novel therapeutic treatments for vascular tumors and potentially other diseases.
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