Pilot and Feasibility Program - PKD Center
New RFA posted 2/7/17
> View the RFA (.pdf format)
The Kansas PKD Research and Translation Core Center at the University of Kansas Medical Center is seeking applications for Polycystic Kidney Disease pilot research grants with the intent to fund up to three proposals in the amount of $50,000 each, for a duration of 1 to 2 years of funding. Please find the RFA attached. A Letter of Intent is due by March 15th and the full proposal is due April 14th. Questions: Contact Lyn Harris, email@example.com
The Kansas PKD Research and Translation Core Center will offer three P&F grants funded through the P30 grant, plus two additional, targeted P&F grants funded by institutional matching dollars. Offering five P&F grants per year, locally and nationally, will maximize the development of research related to the Core Center theme and will accelerate the growth of the Biomedical Research Cores and the training of new PKD physician-scientists. The P&F grants being offered by the Kansas PKD Core Center are:
- Three P30 Pilot & Feasibility grants per year (internal and external) with a focus on the Kansas Core Center theme "Target identification for PKD therapy development."
Status: Three pilot projects were awarded on 9/15/2015:
- "Does the O-GlcNAc post-translational modification regulate the development of PKD and can it be used as an early-stage biomarker for PKD?"
PI: Chad Slawson, Ph.D.
Assistant Professor to the Department of Biochemistry and Molecular Biology
University of Kansas Medical Center
Abstract: O-GlcNAcylation is a ubiquitous post-translational modification of a single N-acetylglucosamine sugar attached to serine or threonine residues in nuclear or cytoplasmic proteins. O-GlcNAc is involved in the regulation of many cellular processes including transcription, bioenergetics, signaling, and cell cycle progression. Preliminary data demonstrate that cellular O-GlcNAcylation is altered as cystogenesis proceeds, and urine from PKD mice have a significant increase in O-GlcNAcylated proteins compared to control mice, potentially serving as a novel biomarker of disease development. These data suggest an important role for OGlcNAcylation in the progression of PKD and provide a novel potential biomarker to measure disease progression. Aim 1 will identify O-GlcNAc regulated genes in cystogenesis, with the objective being to understand how O-GlcNAcylation regulates genes during cystogenesis. These data will provide new information on genes regulated by O-GlcNAcylation that are altered in cystogenesis, and will support the argument that abnormal O-GlcNAcylation may be responsible for misregulation of genes whose expression is altered during PKD. Aim 2 will identify O-GlcNAcylated biomarkers during cystic kidney development, with the objective being to determine the expression of O-GlcNAcylated proteins in urine and serum during the course of disease development. These experiments will also identify O-GlcNAcylated proteins increased in PKD, and the sites of modification. Potentially, these studies could lead to the development of an O-GlcNAc site-specific antibody that could be used in a simple and sensitive test for PKD development and progression.
- "Potential role of the NLRP3 inflammasome in the cystic progression of PKD"
PI: Katherine Swenson-Fields, Ph.D.
University of Kansas Medical Center
Abstract: NLRP3 is part of an innate immune response signaling module (the NLRP3 inflammasome) that is responsive to both microbial and nonmicrobial stimuli and that is an important mediator of tissue injury. Activation or overexpression of NLRP3 in response to microbial products or to host-derived cellular products following sterile injury, promotes its oligomerization and the recruitment of the adaptor protein ASC and the protease caspase-1 to form a protein complex termed "the NLRP3 inflammasome." This complex, once formed, induces caspase-1 activation and cleavage of cellular substrates such as pro-IL-1β and pro-IL-18, both of which are major mediators of the proinflammatory cytokine response leading to apoptosis and necrosis in surrounding tissues and mediate the influx of inflammatory neutophils and monocytes to the site of injury. In addition to expression in immune cells, NLRP3 and other components in the NLRP3 inflammosome are expressed in renal tubular epithelial cells. Aim 1 will characterize the expression levels of NLRP3 inflammasome component proteins (NLRP3, ASC, caspase 1) in ADPKD and non-cystic human kidneys. Aim 2 will measure the levels of IL-1β and IL-18 in the urine and urinary exosomes from ADPKD patients. Aim 3 will determine the contribution of NLRP3 to injury-induced accelerated cystic disease in PKD mouse models. These studies will provide the basis for future research focused on understanding whether NLRP3 effects on cystic disease progression are mediated through the NLRP3 inflammosome/IL-1β/IL-18 axis and may provide support for this pattern recognition receptor as a viable target for therapy to slow disease progression.
- "Role of the Hippo kinase pathway in hepatic cyst growth and pericystic fibrosis in autosomal recessive polycystic kidney disease"
PI: Michele Pritchard, Ph.D.
Assistant Professor in the Department of Pharmacology, Toxicology and Therapeutics
University of Kansas Medical Center
Abstract: Polycystic liver diseases (PLD) are genetic diseases of various etiologies characterized by the development and growth of fluid-filled cysts originating from the biliary epithelium; ductal plate malformation which occurs during biliary tree development is responsible for initiating cystogenesis. The term "cholangiociliopathies" refers to the fact that the products of the genes mutated in PLDs are important in the structure and function of primary cilia found on cholangiocytes. In autosomal recessive polycystic kidney disease (ARPKD), mutations in PKHD1 account for both kidney and liver cysts as well as associated fibroproliferative disease. Importantly, three recent studies suggest that altered Hippo kinase pathway function is associated with cystic kidney and liver disease in mouse and man; complete dissection of the molecular pathways involved in Hippo kinase perturbation remains unknown. Our preliminary data using the PCK rat revealed a robust increase in Yap protein accumulation in livers from PCK rats by Western blotting. Using immunohistochemistry, we observed increased Yap nuclear staining in the flattened CWEC. Consistently, the increased hepatic Yap and nuclear Yap localization was associated with an equally robust increase in the Yap target genes surviving and connective tissue growth factor (CTGF). Yap nuclear localization was also associated with proliferation in CWEC. Importantly, we found that Yap is increased in livers from PKD patients, supporting the relevance of our findings in the PCK rat to human disease. Based on these initial data, we propose to test the hypothesis that perturbed Hippo kinase pathway function favoring Yap activity is a critical regulator of hepatic cyst expansion and fibrosis in CHF in ARPKD. Aim 1 will demonstrate that Yap activity is required for cyst expansion and fibrosis in CHF/ARPKD. Aim 2 will determine the mechanism by which the Hippo kinase pathway is inhibited promoting CWEC proliferation.
- One Department of Internal Medicine/Kidney Institute P&F grant for $50k in directs per year that will be focused on clinically oriented PKD translational research by junior faculty in any of the medicine subspecialties.
Status: Reena Rao, Ph.D., was awarded this pilot grant for her project titled, "Vasopressin Signaling: A Common Pathogenic Process in Polycystic Kidney Disease and Renal Cell Carcinoma"
- One KU Cancer Center Pilot & Feasibility grant for $50k in directs per year (internal) on the relationship between PKD and cancer to take advantage of rapid advances in targeted therapy development in the cancer field.
Status: Jeremy Chien, Ph.D., was awarded this pilot grant for his project titled, "FoxM1 Pathway in Polycystic Kidney Disease"
- An additional Pilot & Feasibility grant of $50k in directs was also awarded to Aron Fenton, Ph.D. for his project titled, "Regulations of M2-pyruvate Kinase control of Warburg Metabolism of Polycystic Kidney Disease and Cancer."
Feb 16, 2017