Environmental Protection Agency, “Human models for analysis of pathways (human MAPs) center” (2014-2018). Sorenson, Senior Scientist
NIH-NEI (R24 EY022883), “Novel antiangiogenic peptides for treatment of exudative AMD” (2013-2018). Sorenson, Co-Investigator
NIH-NHLBI (R01 HL113870), “FGF signaling in lung maturation and response to injury” (2012-2017). Sorenson, Co-Investigator
NIH-NEI (R21 EY023024), “Bcl-2 and ocular neovascularization” (2012-2015). Sorenson, PI
Retina Research Foundation, “Retinal vessel rarefaction and bim expression” (2013). Sorenson, PI
UW-Madison/UW-Milwaukee Intercampus Research Incentive Grant, “Oxidative stress detection in bronchopulmonary dysplasia” (2012-2013). Sorenson, PI
NIH-NEI (RC4 EY021357), “Integrated multidisciplinary strategies for detection of diabetic retinopathies” (2010-2013). Sorenson, Co-Investigator
National Institutes of Health
Bcl-2 protects cells from apoptosis initiated by a variety of stimuli including loss of cell adhesion. Mice deficient in bcl-2 (bcl-2 -/-) develop renal hypoplastic/cystic dysplasia a condition that leads to significant morbidity and mortality in children. The precise mechanism of action of bcl-2 has not been elucidated. Our hypothesis is that early embryonic expression of bcl-2 facilitates morphogenesis by supporting survival of precursor cells allowing them to be less adherent and migratory without the threat of apoptosis. Bcl-2 may facilitate survival of precursor cells and/or play a more “active” role during morphogenesis by interacting with other proteins such as paxillin. Our data demonstrate that paxillin interacts with the bcl-2 BH4 domain in embryonic kidneys. The bcl-2 BH4 domain is sufficient and necessary for its cell survival activity. Bcl-2 with the BH4 domain deleted lacks the survival function but still avidly binds to other bcl-2 family members. We will determine the domain(s) of paxillin that interact with bcl-2 and their influence on cell adhesive mechanisms during kidney development. Our preliminary data indicate that ureteric bud (UB) branching morphogenesis is adversely affected in bcl-2 -/- mice. Metanephroi from bcl-2 -/- mice undergo decreased UB branching in organ culture and bcl-2 -/- UB cells fail to undergo branching morphogenesis in collagen gels. Furthermore, wild-type embryonic kidneys incubated with bcl-2 BH4 domain peptide exhibit defective UB branching morphogenesis. We will examine the role bcl-2 plays during UB branching. Does aberrant UB branching contribute to excessive apoptosis of the metanephric blastema in bcl-2 -/- mice? We will determine whether the abnormalities of renal development in bcl-2 -/- mice is primarily or exclusively the result of the absence of bcl-2 in the UB or metanephric mesenchyme. Therefore, understanding the normal functions of bcl-2 during nephrogenesis and the consequences of its interaction with paxillin will give us important insight into kidney morphogenesis and pathogenesis.
American Heart Association
Nearly half of the new cases of end stage renal disease in the United States are due to diabetic nephropathy. Diabetes predominantly affects the microvascular circulation of the retina and kidney resulting in a range of structural changes unique to these tissues. These changes lead to hyper-proliferation of endothelial cells (EC) and abnormal vascular functions in the retina and kidney with resulting loss of vision and renal function. We have shown that thrombospondin-1 (TSP1), a potent endogenous inhibitor of angiogenesis, is present in vitreous and aqueous humor of normal eyes, but it is absent in diabetic eyes. Our hypothesis is that decreased production of TSP1 promotes the development and progression of renal vasculopathies during diabetes. Our recent studies with a novel diabetic mice model (Akita/+TSP1-/-) developed in our laboratory, indicate that lack of TSP1 exacerbates the development and progression of diabetic retinopathies. However, TSP1’s effect on renal vasculature and the development and progression of diabetic nephropathies require further investigation. Here we propose to determine the impact lack of TSP1 has in the renal vasculopathies associated with the onset and progression of diabetes. We will determine whether changes in TSP1 expression occur during diabetes in Akita/+ mice, and if diabetic mice that lack TSP1 (Akita/+TSP1-/-) are more prone to kidney vasculopathies associated with diabetes. We will identify and confirm the role of TSP1 in vascular abnormalities using kidney EC isolated from mice with diabetes in either the presence or absence of TSP1. We will determine whether lack and/or knockdown of TSP1 in Akita/+ renal EC affects their adhesive and migratory properties and ability to undergo capillary morphogenesis. Delineation of TSP1’s role in diabetic vasculopathies will aid the development of effective treatments which are effective in inhibiting tubular and mesangial expansion and not detrimental to the retinal vasculature.
NIH-NIDDK (P50 DK065303), “The role of BCL-2 during development and branching morphogenesis of the prostate” (2004-2005). Sorenson, Pilot Grant PI
American Heart Association (Beginning Grant-in-Aid), “Cell adhesive mechanisms in renal maturation and cyst formation” (2003-2005). Sorenson, PI