Grants We Funded

Abstract
Lymphedema is a common condition affecting nearly 5 million Americans. One third of patients who undergo lymph node removal for cancer treatment will develop lymphedema, which is characterized by scarring, inflammation and fat deposition. The pathogenesis of lymphedema is still largely unclear, which has led to a lack of effective and targeted treatment options. We have demonstrated that lymphedematous tissue is populated by increased adipose tissue, dilated and dysfunctional lymphatic vessels, dense collagen deposition and prominent inflammation. We have also shown that lymphatic fluid stasis potently upregulates the expression of fat differentiation markers (i.e. PPAR-y, CEBP-a). We hypothesize that lymphatic stasis induces chronic inflammation that drives adipose deposition by adipose cell hypertrophy, mesenchymal stem cell (MSC) migration and adipogenesis. Our objective is to determine how adipocytes are regulated in the setting of lymphedema. Our specific aims are: Aim 1: Determine how obesity and lymphatic stasis are related. Aim 2: Determine how CD4+ cells regulate adipogenesis. The objective of our first aim is to define the relationship between obesity and lymphedema. We anticipate that lymphatic fluid stasis will contribute to adipose deposition in lymphedema and obesity. Experiments will be performed using a microsurgical mouse tail model of sustained lymphedema and outcomes of lymphatic function, fat deposition and inflammation will be measured. The objective of our second aim is to determine if CD4+ cells can promote adipogenesis. We anticipate that CD4+ T cell differentiation resulting from lymphatic stasis will cause MSC migration, adipocyte hypertrophy and adipose differentiation. We will perform tail operations on nude mice (no T cells) and utilize adoptive T cell transfer to test our hypothesis. We hope to elucidate the role of adipose tissue in the development of lymphatic fluid stasis as a means to develop targeted therapies for lymphedema.