In this thesis, two potential therapeutic targets for diabetic nephropathy were dentified and investigated. First, we show that glomerular clusterin is upregulated in diabetic nephropathy and... Show moreIn this thesis, two potential therapeutic targets for diabetic nephropathy were dentified and investigated. First, we show that glomerular clusterin is upregulated in diabetic nephropathy and demonstrated that recombinant clusterin protein can protect the podocytes against oxidative stress in vitro. Second, we reveal that hCN1 overexpression accelerated and aggravated diabetic nephropathy in BTBR ob/ob mice. We also studied two novel zebrafish models to investigate chronic kidney disease. We showed that lepb-/- adult zebrafish have the early signs of human diabetic nephropathy, and we demonstrated that ctns mutant adult zebrafish have the kidney pathologic features of human nephropathic cystinosis. Show less
Triple-negative breast cancer (TNBC) constitutes a small subtype (~15%) of breast cancer, but causes the majority of breast cancer-related deaths. As defined by the absence of ER and PR expression... Show moreTriple-negative breast cancer (TNBC) constitutes a small subtype (~15%) of breast cancer, but causes the majority of breast cancer-related deaths. As defined by the absence of ER and PR expression and HER2 overexpression, TNBC is not curable by hormone receptor or HER2-targeted therapies. Furthermore, TNBC is highly heterogeneous and most aggressive. To date, cytotoxic chemotherapy remains the mainstay in the management of TNBC. Despite the initial response to the standard-of-care chemotherapy, TNBC often exhibits intrinsic or acquired drug resistance, and subsequently, recurs in local and distal organs. Targeted therapies have long been pursued for the treatment of TNBC, but rarely demonstrate satisfactory clinical outcomes. Therefore, improved understanding of the intricate biological basis underlying TNBC insensitivity to targeted agents and defining new therapeutic opportunities are of the upmost importance. The aim of the studies presented in this thesis was to systematically identify gene/kinase susceptibilities of refractory TNBC cells, and reveal novel potent targeted therapies for TNBC as monotherapy or in combination with approved kinase drugs. Show less