Wednesday, January 15, 2025
1/15/2025
Project Summary With modern advances in medicine, our average lifespan is increasing. However, advanced age is often accompanied by chronic diseases Our immune systems frequently plays a central role in the development of chronic diseases and T cells play a critical role in the immune system, providing protection against infection and cancer. The thymus, the primary organ for T cell development, however, undergoes a profound age-dependent atrophy, a process called thymic involution. Thymic involution results in T cell immunodeficiency, leading to increased susceptibility to infection and cancer, and difficulty in establishing protective immunity via vaccinations. Currently, there is no effective way to prevent or reverse T cell immunodeficiency among older adults. T cell development in the thymus is dependent on the thymic microenvironment, in which thymic epithelial cells (TECs) are the major components. However, TECs undergo qualitative and quantitative loss that is the major factor responsible for thymic atrophy. FOXN1 is a pivotal regulator for TEC development and maintenance, and we have shown that recombinant (r) FOXN1 fusion protein that contains FOXN1 and a protein transduction domain (PTD) can translocate from the cell surface into the cytoplasm and nucleus. Intrathymic (i.t.) injection of the rFOXN1 fusion protein into mice increases the number of TECs, and, consequently, enhances thymopoiesis and increases the number of T cells in the periphery. However, the i.t. injection route is impracticable for human application. Development of a more practicable regimen in term of the route of administration is necessary. The goal of this proposal is to develop new rFOXN1 fusion proteins that can migrate into the thymus to enhance thymopoiesis after intravenous (i.v.), intramuscular (i.m.), or subcutaneous (s.c.) injection into old mice. In the R21 phase, we will produce rFOXN1 fusion proteins containing FOXN1-PTD and thymus targeted peptides, or thymus/TEC specific receptor or antibody (Aim 1). We will then determine the ability of the rFOXN1 fusion proteins to migrate into the thymus when injected i.v., i.m. or s.c. (Aim 2), and to increase the number of TECs and T cells in old mice (Aim 3). If the R21 milestones are met, the R33 phase will be undertaken. Aim 4 will further characterize the thymus and the peripheral T cell function in the rFOXN1 fusion protein-treated old mice. In Aim 5, we will determine whether T cells in rFOXN1 fusion protein-treated old mice are immune tolerant to self-antigens to prevent autoimmunity. Aim 6 will analyze rodent toxicology and pharmacokinetics of a lead rFOXN1 fusion protein. Our long-term goal is to use the lead rFOXN1 fusion protein to prevent and treat T cell immunodeficiency in older adults, thus leading to improved healthcare outcomes and mortality rates.
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