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2012 Pilot Project Award

Elisa Boscolo, PhD
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.

This project proposes the establishment of a murine VM model that will help us determine the mechanisms of abnormal venous channel formation. Our end-goal is to test and discover novel efficient treatments to normalize the pathological VM vasculature and avoid a rebound of the disease.

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, MD, PhD
WNK1/HSN2: A novel kinase regulator of sensory transduction mutated in an orphan disease featuring congenital insensitivity to pain and temperature
The serine-threonine kinase WNK1 is unique in that mutations in two different isoforms of its encoding gene (PRKWNK1) cause separate orphan diseases, underscoring the critical and diverse role of this gene for human physiology1. A decade ago, mutations in the isoform of WNK1 predominantly expressed in kidney were detected in a rare inherited form of salt-sensitive hypertension called pseudohypoaldosteronism type 2 (PHA2). The molecular characterization of this disease made possible by study of a mouse model of the disease provided insight into the function of WNK1, helped improve the diagnosis and treatment of patients with PHA2, and also identified WNK1 as a novel potential target for the development of a novel class of antihypertensive drugs for the general population. Recently, mutations in a different isoform of WNK1 (termed “WNK1/HSN2”) have been detected in another orphan disease, hereditary sensory and autonomic neuropathy type 2 (HSAN2). This disease is a devastating neuropathy with early childhood onset, characterized by a progressively-reduced sensation to pain, temperature, and touch, leading to ulcerations of the hands/feet that often require amputations5. Currently, the pathogenesis of HSAN2 is unknown and there is no cure. Interestingly, WNK1/HSN2 is expressed exclusively in the spinal cord and peripheral nervous system; however, the upstream regulators, downstream molecular targets, and the mechanism by which mutations in WNK1/HSN2 cause disease all remain unknown. A mouse model of HSAN2 harboring disease-causing mutations in WNK1/HSN2 would be a valuable tool to test different models of disease pathogenesis, as well as to evaluate future therapies. 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
Primary immunodeficiency (PID) include a group of genetic diseases that affect development and function of the immune system. In particular, defects in the RAG genes cause some of the most severe forms of PIDs, with recurrent and severe infections and failure to thrive. Milder forms of the disease may present with autoimmunity and organ damage that dramatically reduce the quality of life and reduce life span. We will use a novel assay to investigate the cellular and molecular bases that account for the variable clinical presentation of RAG deficiency.

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.

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