Modifiers of Cyst Progression in Polycystic Kidney Disease

Summary

Principal Investigator: Phillip Darwin Bell
Abstract: DESCRIPTION (provided by applicant): Polycystic kidney disease (PKD) is a "ciliopathic" disease since the loss of cilia or mutations in proteins involved in the function of cilia lead to renal cystic development. During embryonic development, deletion of cilia or mutations in cystoproteins such as polycystin 1 and 2 lead to PKD. However, in the adult animal, using conditional floxed alleles, to knockout cilia or delete cystoproteins, development of significant cystic disease only occurs after a number of months. The reason for this delay is not clear but it has provided a model to study factors or conditions that modify the initiation and progression of cystogenesis. This has led to the concept of a "third hit" in which an environmental influences, physiological adaptive responses, or associated pathophysiological conditions initiates and accelerates cystogenesis. Previous work has shown that acute kidney injury can accelerate cystogenesis. Recently we have shown that reduced renal mass also accelerates the formation of cysts. Finally, it has been reported in humans that kidney size, which is an index of cystic burden, is doubled in diabetic versus non-diabetic autosomal dominant PKD patients. Thus, hypertrophic signaling and hyperglycemia may be two extremely important regulators of disease progression in PKD. Hypothesis: That the presence of reduced renal mass or elevated blood glucose levels result in the initiation and acceleration of cystogenesis in mouse models of PKD. In addition, lack of cilia or mutations in cystoproteins may affect the renal adaptive response to hypertrophy and hyperglycemia Specific objectives: (1) investigate reduced renal mass (nephrectomy), hyperglycemia (diabetes), or both as third hits that accelerate cystogenesis;(2) determine if cilia or cystoproteins modulates renal hypertrophy and affects disease progression thereby leading to accelerated diabetic nephropathy;and (3) unravel the complex signaling processes that result in cystogenesis. Determine how these pathways are altered in the presence of hyperglycemia and hypertrophic signaling. Relevance: In ADPKD, cyst progression is highly variable and understanding what triggers initiation and what regulates cyst progression has become a major focus in PKD research. The studies outlined in this application will provide new and important information on what regulates the onset and progression of cystogenesis. Procedures to be used: Adult mice with and without PKD will be studied in presence or absence of nephrectomy to reduce renal mass or after induction of diabetes with streptozotocin or in the presence of both conditions. Light and electron microscopy will be used to study cystic development and assess pathological changes in kidney and other organs and in cell culture models. Physiological studies will be performed to assess GFR, blood pressure, and proteinuria, Western blot, immunofluorescence, genomic analysis will be used to evaluate the complex signaling pathways that are activated in these models. Significance of potential new findings: Only recently has hypertrophic signaling and hyperglycemia been identified as playing critical roles in the initiation and rate of cyst progression in PKD. In addition the role of cilia in controlling structural and functional hypertrophy and in the renal response to diabetes has not been studied. This work may lead to new approaches to arrest or slow the progression of cystic disease. Potential impact on Veterans health care: Autosomal Dominant Polycystic kidney disease affects both males and females of all ethnicities with symptoms beginning between 30 and 40 years of age. It is a devastating disease that usually results in renal failure with treatment options limited to dialysi and transplantation. There are also cardiovascular effects including hypertension and stroke. For reasons that are not clear, the incidence of PKD reported in the VA population is nearly double of that found in the general non- VA population. Thus there is a compelling reason to focus on this disease and its effective treatment or cure, which would greatly benefit the VA patient population.
Funding Period: 2013-04-01 - 2017-03-31
more information: NIH RePORT

Research Grants

Detail Information

Research Grants30

  1. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
  2. Carbon Monoxide: Novel Opportunities for Therapy
    Mark A Perrella; Fiscal Year: 2013
    ..and Specialized Pro-Resolving Mediators Cores: Core A: Administrative Core Core B: Clinical Studies Coordination Core Core C: Lipid Mediator Metabolomics Core D: Carbon Monoxide Delivery in Sepsis and Acute Lung Injury ..
  3. Role of Periostin in Polycystic Kidney Disease
    Darren P Wallace; Fiscal Year: 2013
    ....
  4. Lentiviral Gene Therapy for Sickle Cell Disease and Immunodeficiency Disorders
    Brian P Sorrentino; Fiscal Year: 2013
    ..abstract_text> ..
  5. Innate/Adaptive Immune Interactions in Gut Inflammation
    Sergio A Lira; Fiscal Year: 2013
    ..Overall the focus and interactive nature of the program (20 joint publications in 4 years, 3 additional NIH grants on related areas) provide a solid basis for a productive outcome. ..
  6. Dysregulated Angiogenesis in ADPKD
    BERENICE YOLANDE GITOMER; Fiscal Year: 2013
    ..The results of these studies will impact future research directions in ADPKD. In particular, positive results of the proposed study should inform about the planning of a large, definitive, interventional study in patients with ADPKD. ..
  7. COBRE for Skeletal Health and Repair
    Qian Chen; Fiscal Year: 2013
    ..This multidisciplinary approach is absolutely necessary to develop translational strategies for prevention and treatment of skeletal joint diseases. ..
  8. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  9. Mechanism of eNOS Uncoupling in the Renal Microvasculature
    YVES CLAUDE GORIN; Fiscal Year: 2013
    ..abstract_text> ..
  10. Mechanisms of Health Effects of Exercise in Children
    Dan M Cooper; Fiscal Year: 2013
    ..Collectively, the PPG will promote novel preventive and adjunctive exercise therapies in children with chronic inflammation- therapies grounded in a firm understanding of biological mechanisms. ..
  11. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  12. Ether Lipids, Elcosanoids, and Lung Cell Pathophysiology
    CHRISTINA CARROLL LESLIE; Fiscal Year: 2013
    ..By using multidisciplinary approaches, we will determine the structural identity of lipid mediators, the molecular mechanisms involved in their production and how they function to regulate lung responses. ..
  13. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  14. Role of Protein Acetylation in Diabetic kidney Disease
    John C He; Fiscal Year: 2013
    ..The proposed studies will help us to understand how acetylation of TFs affects their target gene expression in diabetic kidneys and determine whether BrDi could be developed as a new class of drugs to treat patients with DKD. ..
  15. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  16. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
    ..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
  17. MOLECULAR GENETICS OF COAGULATION DISORDERS
    David Ginsburg; Fiscal Year: 2013
    ..This Project will identify key genes in this system that should provide valuable new diagnostic tools as well as suggest novel approaches to treatment. ..
  18. ENDOTHELIN CONTROL OF RENAL HEMODYNAMIC AND EXCRETORY FUNCTION
    David M Pollock; Fiscal Year: 2013
    ..In particular, this Program will investigate a full range of mechanisms that control ET-1 release and receptor specific actions in order to provide clinically relevant information. ..
  19. BIOLOGY OF NEUROENDOCRINE PEPTIDES
    Marc R Montminy; Fiscal Year: 2013
    ..Specifying the contributions of the CRF family of ligands and receptors to the maintenance of homeostasis and to stress-linked allostasis may improve our ability to manage diseases, including mood and metabolic disorders ..
  20. Discovery and Development of Therapeutic Genes for CHF
    H Kirk Hammond; Fiscal Year: 2013
    ..Four Cores will support the Program: Digital Imaging (Dr. Farquhar);Vector Production (Dr. Miyanohara);Translational Systems (Dr. Hammond) and Clinical &Administrative (Dr. Hammond). ..
  21. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..
  22. Urine biomarkers of lupus nephritis pathology and response to therapy
    James C Oates; Fiscal Year: 2013
    ..The long-term goal is to provide clinicians with a qualified biomarker panel coupled with a web-based predictive tool for more accurate diagnosis and therapeutic monitoring of LN. ..