Improving islet transplantation outcome with Akt1

Summary

Principal Investigator: Hongju Wu
Abstract: DESCRIPTION (provided by applicant): Summary Islet transplantation is becoming a potential cure for type 1 diabetes (T1D). However, the limited supply and significant islet loss in the peritransplant period are cast as the major limitations of this treatment strategy. This project is aimed to improve the therapeutic outcome of islet transplantation by introducing constitutively active Akt1 (CA-Akt1) into the insulin producing 2-cells ex vivo. The serine/threonine protein kinase Akt/PKB is the direct downstream target of PI3 Kinase pathway, and has been found to have dual functions of anti-apoptosis and induction of cell proliferation. Relevance of Akt on 2-cell survival and proliferation has been demonstrated in studies of transgenic and knockout mouse models, as well as using pharmacological methods. Nonetheless, in order to realize the therapeutic potential of CA-Akt1, a safe, efficient and specific vector is needed to deliver Akt1 into islet 2-cells ex vivo. In this regard, adenovirus serotype 5 (Ad5)-based vector is of great interest. Our previous studies have demonstrated the modified Ad5 vector, AdRGDpK7, exhibited significantly higher gene transfer efficiency for the human islet cells. We thus propose to employ Ad5RGDpK7 to deliver Akt1 into islet cells ex vivo. To further diminish the potential adverse effect of CA-Akt1, we will restrict exogenous Akt1 expression in 2-cells by employment of 2-cell specific promoter-rat insulin promoter (RIP) to drive Akt1 expression. In addition, we propose to co-express a dual functional modality, HSV-TK, with CA-Akt1 so that it can be used as both a non-invasive imaging modality to follow the transplanted islets and a suicide gene should malignancy occur. Our specific aims are thus: 1) To develop a 2-cell specific, infectivity-enhanced Ad5 vector that allows efficient and specific CA-Akt1 and HSV-TK gene delivery into 2-cells ex vivo;2) To examine the capacity of the Ad5 vector developed above to promote islet survival and proliferation while minimizing transformation, thus enhancing the efficacy of islet transplantation;and 3) To evaluate the safety of the Ad5 vector developed above in the context of islet transplantation. PUBLIC HEALTH RELEVANCE: It is clear that islet transplantation holds great potential for the cure of Type 1 Diabetes. This study seeks to improve the therapeutic outcome of islet transplantation by modifying the islets with protective genes using a highly efficient, specific and safe gene delivery vector. Success of this study is expected to have significant impact in the field of islet transplantation treatment for type 1 diabetes.
Funding Period: 2012-10-15 - 2013-03-31
more information: NIH RePORT

Top Publications

  1. pmc Suppression of intestinal calcium entry channel TRPV6 by OCRL, a lipid phosphatase associated with Lowe syndrome and Dent disease
    Guojin Wu
    Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294 0006, USA
    Am J Physiol Cell Physiol 302:C1479-91. 2012
  2. pmc Regeneration of pancreatic non-β endocrine cells in adult mice following a single diabetes-inducing dose of streptozotocin
    Yanqing Zhang
    Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama, USA
    PLoS ONE 7:e36675. 2012
  3. pmc Gene transfer of active Akt1 by an infectivity-enhanced adenovirus impacts β-cell survival and proliferation differentially in vitro and in vivo
    Robert N Bone
    Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
    Islets 4:366-78. 2012
  4. ncbi Progressive change of intra-islet GLP-1 production during diabetes development
    Thomas J O'Malley
    Endocrinology Section, Department of Medicine, Tulane University Health Science Center, New Orleans, LA, United States
    Diabetes Metab Res Rev 30:661-8. 2014

Research Grants

  1. T Cell Costimulatory Pathways: Functions and Interactions
    Arlene H Sharpe; Fiscal Year: 2013
  2. Epidemiology of Breast Cancer Subtypes in African American Women: a Consortium
    Julie R Palmer; Fiscal Year: 2013
  3. Colorado Nutrition Obesity Research Center
    James O Hill; Fiscal Year: 2013
  4. Center for Molecular Imaging Research at MGH/HMS
    Ralph Weissleder; Fiscal Year: 2013
  5. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
  6. JHU ICMIC PROGRAM
    Zaver M Bhujwalla; Fiscal Year: 2013
  7. Hypoxic Adenosine Responses
    Michael R Blackburn; Fiscal Year: 2013
  8. mt-Nd2 and Resistance to Autoimmune Diabetes
    Clayton E Mathews; Fiscal Year: 2013
  9. A Novel Approach of beta Cell Replacement to Reverse Type I Diabetes in NOD Mice
    Roland M Tisch; Fiscal Year: 2013
  10. MODIFIED POLY(DISULFIDE AMINE)AS A PANCREAS TARGETING POLYMERIC VECTOR
    Sung Wan Kim; Fiscal Year: 2013

Detail Information

Publications4

  1. pmc Suppression of intestinal calcium entry channel TRPV6 by OCRL, a lipid phosphatase associated with Lowe syndrome and Dent disease
    Guojin Wu
    Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294 0006, USA
    Am J Physiol Cell Physiol 302:C1479-91. 2012
    ..In conclusion, OCRL suppresses TRPV6 via two separate mechanisms. The disruption of PI(4,5)P(2) 5-phosphatase activity by Dent-causing mutations of OCRL may lead to increased intestinal Ca(2+) absorption and, in turn, hypercalciuria...
  2. pmc Regeneration of pancreatic non-β endocrine cells in adult mice following a single diabetes-inducing dose of streptozotocin
    Yanqing Zhang
    Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama, USA
    PLoS ONE 7:e36675. 2012
    ..Taken together, our study demonstrated adult α- and δ-cells could regenerate, and both self-duplication and regeneration from endocrine precursor cells were involved in their regeneration...
  3. pmc Gene transfer of active Akt1 by an infectivity-enhanced adenovirus impacts β-cell survival and proliferation differentially in vitro and in vivo
    Robert N Bone
    Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
    Islets 4:366-78. 2012
    ..Nonetheless, the vector evoked the expression and activation of endogenous Akt in the islets, thus offering beneficial bystander effect against STZ-induced diabetes...
  4. ncbi Progressive change of intra-islet GLP-1 production during diabetes development
    Thomas J O'Malley
    Endocrinology Section, Department of Medicine, Tulane University Health Science Center, New Orleans, LA, United States
    Diabetes Metab Res Rev 30:661-8. 2014
    ..This study was aimed to investigate the progressive changes of GLP-1 versus glucagon production in pancreatic islets during the course of diabetes development...

Research Grants30

  1. T Cell Costimulatory Pathways: Functions and Interactions
    Arlene H Sharpe; Fiscal Year: 2013
    ..Overall, this PPG should provide fundamental knowledge for therapeutic manipulation of these important regulatory pathways. ..
  2. Epidemiology of Breast Cancer Subtypes in African American Women: a Consortium
    Julie R Palmer; Fiscal Year: 2013
    ..By pooling our data, specimens, and importantly, expertise to investigate these synergist hypotheses, we will elucidate much of the etiology of aggressive, early onset breast cancers in AA women. ..
  3. Colorado Nutrition Obesity Research Center
    James O Hill; Fiscal Year: 2013
    ..We look forward to continuing to enhance nutrition research within Colorado over the next 5 years. ..
  4. Center for Molecular Imaging Research at MGH/HMS
    Ralph Weissleder; Fiscal Year: 2013
    ....
  5. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..
  6. JHU ICMIC PROGRAM
    Zaver M Bhujwalla; Fiscal Year: 2013
    ..The Career Development Component is structured with the purpose of creating independently funded investigators who will, in the future, become leaders in the field. ..
  7. Hypoxic Adenosine Responses
    Michael R Blackburn; Fiscal Year: 2013
    ..Three Component Projects, Two Scientific Cores and an Administrative Core are planned to facilitate the research goals and interactions of this PPG. ..
  8. mt-Nd2 and Resistance to Autoimmune Diabetes
    Clayton E Mathews; Fiscal Year: 2013
    ..The studies, as proposed, will provide meaningful data on both the early apoptotic signals that result in human beta cell death as well as insights into how ND2a protects human beta cells. ..
  9. A Novel Approach of beta Cell Replacement to Reverse Type I Diabetes in NOD Mice
    Roland M Tisch; Fiscal Year: 2013
    ..Experiments will also be included to assess the effects of ectopic prolactin expression on inflammation in the pancreas. ..
  10. MODIFIED POLY(DISULFIDE AMINE)AS A PANCREAS TARGETING POLYMERIC VECTOR
    Sung Wan Kim; Fiscal Year: 2013
    ..PUBLIC HEALTH RELEVANCE: The objective of this proposal is to create a rational, pancreas-specific targeting vehicle for soluble RAE-1 expression to deter autoimmune responses for the treatment of type-1 diabetes. ..
  11. Cardiac Myosin Binding Protein-C: Structure, Function, and Regulation
    David M Warshaw; Fiscal Year: 2013
    ..abstract_text> ..
  12. Center for Neuroplasticity at the University of Puerto Rico
    Steven N Treistman; Fiscal Year: 2013
    ..This UPR COBRE Center should define pathways and benchmarks for basic and translational research across the UPR system for the next decades. ..
  13. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
    ....
  14. Center for Gene Therapy of Cystic Firbosis
    John F Engelhardt; Fiscal Year: 2013
    ..These efforts have led to numerous basic and applied research findings that have enhanced the utility of gene therapies to both study and treat genetic diseases. ..
  15. Protein-Releasing Microporous Scaffolds for Cell Replacement Therapy
    Lonnie D Shea; Fiscal Year: 2013
    ..These scaffolds provide a support for cell growth and can deliver proteins which will be to enhance cell survival and function following islet transplantation. ..
  16. Directing Tumor-specific T cells to Tumors
    Pawel Kalinski; Fiscal Year: 2013
    ..abstract_text> ..
  17. Vanderbilt Diabetes Research Center
    Alvin C Powers; Fiscal Year: 2013
    ..Because of the VDRTC and the environment it creates, VDRTC-affiliated investigators have made important scientific contributions related to diabetes, obesity, and metabolism. ..
  18. Hepatocyte Growth Factor and the Pancreatic Beta Cell
    Adolfo Garcia-Ocana; Fiscal Year: 2013
    ....