2012 Pilot Project Award
Elisa Boscolo，博士
Venous Malformation (VM): murine model to identify therapies to target aberrant venous development
Venous malformation (VM) is the most frequent malformation referred to specialized vascular anomaly centers. VMs appear in children and are often problematic and disfiguring. VM lesions are composed by widened, abnormally shaped veins. No targeted therapies are available, and treatments for VM are very limited, including only sclerotherapy and reconstructive surgery. After treatment, lesions often recur.
该项目提出建立一个鼠VM模型，该模型将帮助我们确定异常静脉通道形成的机制。我们的最终目标是测试和发现新型有效治疗方法，以使病理VM脉管系统正常化并避免疾病的反弹。
Janet Sue Chou MD
The role of transferrin 1 in lymphocyte activation and serologic memory
An intact immune system depends on molecular signals between and within immune cells to effectively protect the host from infections. Human immunodeficiencies are disorders in which the immune system is unable to respond appropriately to infectious agents or vaccines, leading to recurrent infections that can be fatal. We have identified the first human immunodeficiency caused by a mutation in the gene encoding transferrin receptor 1 (TfR1), a receptor known to be important for importing iron into cells. Patients with this mutation have recurrent infections in the sinuses and lung and are unable to form a long-lasting immune response. We are able to correct some, but not all, of the immune defects by adding a cell-permeable form of iron to bypass the defective TfR1. This suggests that TfR1 has another role in the immune system other than iron import.
Therefore, we propose a novel model of TfR1 function as a receptor with dual roles in activating immune cells: iron import and molecular signaling. We will make a mouse model of this disease to investigate the specific defects leading to this immunodeficiency. These studies will identify how this mutation in TfR1 causes this disease and demonstrate how TfR1 is important for the formation of a normal immune response. In determining the contribution of TfR1 to a normal immune response, these studies may identify new approaches for vaccine development.
Kristopher Kahle，医学博士，博士
WNK1/HSN2：一种新型的感觉转导的激酶调节剂，在孤儿疾病中突变，以先天性对疼痛和温度不敏感
丝氨酸 - 苏氨酸激酶WNK1是独一无二的，因为其编码基因的两个不同同工型的突变（PRKWNK1）引起了单独的孤儿疾病，强调了该基因对人类生理学的关键和多样性作用。十年前，以一种罕见的遗传形式的盐敏感性高血压（称为pseudohypoaldosterism）型2型（PHA2）以一种罕见的遗传形式的盐敏感高血压（PHA2）检测到WNK1的同工型中主要表达的WNK1的突变。通过研究该疾病的小鼠模型，该疾病的分子表征成为可能，从而深入了解了WNK1的功能，有助于改善PHA2患者的诊断和治疗，并确定WNK1是开发A的新型潜在目标。一类新型的降压药给普通人群。最近，在另一种孤儿疾病，遗传性感觉和自主神经病2型（HSAN2）中检测到了WNK1不同同工型（称为“ WNK1/HSN2”）的突变。这种疾病是一种毁灭性的神经病，幼儿发作，其特征是逐渐减少疼痛，温度和触摸的感觉，导致手/脚的溃疡通常需要截肢5。当前，HSAN2的发病机理尚不清楚，无法治愈。有趣的是，WNK1/HSN2仅在脊髓和周围神经系统中表达。然而，上游调节剂，下游分子靶标以及WNK1/HSN2引起疾病突变的机制均尚不清楚。在WNK1/HSN2中携带引起疾病突变的HSAN2的小鼠模型将是测试不同疾病发病机理的重要工具，并评估未来的疗法。 We now have such a model and wish to characterize it in detail using a battery of histopathological, neurobehavioral, and electrophysiological assays in an effort to develop a mouse model of HSAN2. We anticipate this work will shed light into the normal function of WNK1/HSN2 and help define the molecular pathogenesis of HSAN2 to provide a basis for rational therapeutic intervention. Moreover, insights from these studies may benefit other more common neuropathies with similar characteristics as HSAN2, such as diabetic, HIV- and Hepatitis C-related neuropathies, as well as other complex pain syndromes.
Yu Nee Lee PhD
From Molecular Mechanism of RAG1 Mediated Primary Immunodeficiency to Gene Correction
原发性免疫缺陷（PID）包括一组影响免疫系统发育和功能的遗传疾病。特别是，抹布基因的缺陷引起了一些最严重的PID形式，复发和严重的感染以及未能繁殖。这种疾病的温和形式可能会出现自身免疫性和器官损害，从而大大降低生活质量并降低寿命。我们将使用一种新颖的测定法研究占RAG缺乏临床表现的可变临床表现的细胞和分子碱基。
Treatment of RAG deficiency is based on bone marrow transplantation, but mortality and long-term complications remain a significant problem. Gene therapy has been successfully used to treat some severe forms of PID, however leukemia has been observed in several patients as the result of insertion of the normal gene in dangerous areas of the genome. We will use cellular models of human RAG1 deficiency to investigate the ability of engineered proteins to specifically target the RAG1 gene and permit correction of the gene error. If successful, this will represent an important step toward the development of a customized therapy for severe forms of PID.