In Graves disease, the body's immune system attacks the thyroid gland, causing abnormal levels of thyroid hormone production. For reasons that are unknown, one of the primary sites of the pathology that occurs in Graves disease is the orbit, including the muscles that move the eyes and the orbital fat. Additionally, the inflammation associated with this condition leads to extraocular muscle enlargement and adipogenesis, which results in proptosis and eyelid edema. Graves eye disease, also called thyroid eye disease (TED), is a potentially sight-threatening condition in which approximately 10-20 percent of patients with this systemic autoimmune disorder will develop severe inflammation in the eye sockets that can lead to disabling double vision or irreversible vision loss. Currently, there are no specific treatments for TED beyond steroids and/or surgical decompression of the orbits, which involves breaking of the bones surrounding the orbit. To date, research has centered on identifying what makes the orbit a unique, vulnerable environment for this systemic condition, as other areas in the body with fat deposits fail to exhibit similar inflammatory changes. Previous studies suggest that under normal conditions, orbital tissues have blood vessels, but there is an absence of lymphatic vessels within the orbital fat surrounding the eye. In contrast, other fat deposits within the body contain both blood and lymphatic vessels. Based on this, we hypothesize that the orbital inflammation and edema that occurs in TED may be caused by the inability to drain fluid from the interstitial space, as there are no lymphatic vessels within the orbital tissue. While TED is most often characterized by chronic inflammation, episodes of acute inflammation that may be vision threatening can occur. Preliminary data from our laboratory demonstrates that blood vessel proliferation and new lymphatic channel formation occurs within the orbit during the acute inflammatory episodes in TED. Thus, we believe that regulation of blood and lymphatic vessel formation within the orbit could ameliorate the effects of acute orbital inflammation. To test this, we propose to determine the novel molecular mechanisms underlying the formation of blood and lymphatic vessels within the human orbit (Aim 1) and to investigate whether the regulation of new blood vessel formation and/or promotion of lymphangiogensis can reduce the orbital edema phenotype observed in an oxazolone mouse model of acute orbital inflammation developed in our laboratory (Aim 2). At the conclusion of these studies, we will have expanded our knowledge of the molecular mechanisms underlying vasculogenesis within the orbit by identifying potential targets responsible for the regulation of orbital vasculogenesis. It is hoped that the identification of these novel targets could lead to alternative therapies for the treatment of the acute inflammation that occurs in TED.
Graves eye disease, also called thyroid eye disease, is a potentially sight-threatening condition in which approximately 10-20 percent of patients will develop severe inflammation in the eye sockets (orbits) that can lead to disabling double vision or irreversible vision loss. As only the orbit seems to be affected by the inflammatory changes caused by thyroid eye disease, we hypothesize that the lack of lymphatic vessels creates an inability to drain fluid from the orbit resulting in swelling caused by inflammation. This project investigates the mechanisms responsible for the formation of new blood and lymphatic vessels within the human orbit and investigates whether the regulation of new blood and lymphatic vessel formation can reduce the orbital swelling in a mouse model of acute orbital inflammation.
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