Research Projects & Grants

Federal

  • LLU-NIH Initiative for Maximizing Student Development, Role: Other Significant Contributor, National Institute of General Medical Sciences/NIH/DHHS, (01/2018 - 12/2023) Status: Closed
  • Palmitic Acid Regulation of Dendritic Cell Toll-Like Receptor 4 Signaling, Role: Co-Sponsor, National Institutes of Health/DHHS, (09/2013 - 09/2015) Status: Closed
  • LLU Center for Health Disparities Research, Role: Co-Investigator, National Institute of Minority Health and Health Disparities/NIH/NIMHD, (07/2012 - 01/2020) Status: Closed
  • Vaccinia virus vaccine for Type I diabetes, National Institute of Diabetes and Digestive and Kidney Diseases/NIH/DHHS, (09/2003 - 09/2004) Status: Closed
  • Vaccinia virus vaccine for type 1 diabetes, National Institutes of Health/DHHS, (09/2002 - 07/2008) Status: Closed
  • Plan-based vaccine against anthrax lethal toxin, National Institutes of Health/DHHS, (07/2002 - 06/2003) Status: Closed

Internal

  • Vaccine Therapy for Tissue Specific Autoimmunity, Role: Principal Investigator, LLU School of Medicine, (04/2016 - 03/2020) Status: Closed
  • Research and Education Fund, Role: Principal Investigator, LLU Dept. of Physiology & Pharmacology, (01/2007 - 12/2016) Status: Closed
  • Plant-based mucosal vaccines against anthrax toxin, LLU School of Medicine (BRSG), (01/2002 - 12/2002) Status: Closed
  • GRASP:Oral SlgA immunoglobulin treatment to prevent gastrointestinal mucositis caused by chemotherapy, Role: Co-Investigator, LLU - GRASP, (01/2025 - 12/2026) Status: Awarded

Other Research

  • NIH R21 Proposal: Multicomponent Vaccine Immunothrapy for Type 1 Diabetes, Application number: 1 R21 DK082931-01, Submitted: Jan 28, 2008;  Budget: $275,000. Direct costs, for 2 years,  Priority Score 281. Collaborators: Dr. J. Vivekananda, Dr. Alan Escher, Dr. Nathan Wall:   Single therapeutic strategies can provide short term suppression of organ-specific autoimmunity. However, few individual therapies have demonstrated effective and durable disease intervention. Integrated strategies involving incorporation of several interventional modalities show promise for more effective and sustainable suppression of autoimmune disease inflammation. Here we propose a novel multicomponent immunological tolerization strategy that incorporates IL-12 DNA aptamers and the cholera toxin B subunit (CTB) immunomodulator for enhanced autoantigen mediated suppression of type1 diabetes. The efficacy of this combinatorial vaccination strategy will be assessed by analysis of insulitis and hyperglycemia progression in non-obese diabetic (NOD) mice after oral inoculation with aptamers that bind IL-12 or its receptor (IL-12R), and edible plant produced CTB-insulin (INS) fusion protein. Mechanisms underlying IL-12/R aptamer and CTB-INS enhancement of immunological tolerance in immunized mice will be clarified by flow cytometric analysis of Peyer’s patches, mesenteric lymph node, and pancreatic dendritic cell populations and by ELISA quantification of DC intracellular IL-12 and IL-10 cytokines. In parallel experiments,  the effects of aptamer and CTB-INS on stimulation of regulatory T cell expansion and activation will be assessed by flow cytometric analysis of CD4+ T cell FOXP3, GITR and CTLA-4 marker protein induction and by ELISA quantification of autoantigen challenged T cell secreted IL-10 and TGF-β. Determination of the fundamental mechanisms underlying aptamer and CTB enhancement of autoantigen mediated immunological tolerance will establish a basis for oligo-array and RNAi identification of DC and Treg genes involved in coordination of aptamer and immunomodulator enhanced diabetes suppression. The proposed experiments will provide a foundation for development of coordinated multicomponent strategies for restoration of immunological homeostasis in patients with type 1 diabetes and other chronic organ specific inflammatory diseases that contribute to increased mortality especially in populations with disparities in health outcomes. (01/2008 - 12/2009)
  • Juvenile Diabetes Foundation: Innovative Research Proposal: Aptamer Immunotherapy for Type 1 Diabetes, Submitted 06/25/08, Budget #100,000. for 1 yr. Single therapeutic strategies can provide short term suppression of organ-specific autoimmunity. However, few individual therapies have demonstrated effective and durable disease intervention. Integrated strategies involving incorporation of several interventional modalities show promise for more effective and sustainable suppression of autoimmune disease inflammation. Here we propose a novel multicomponent immunological tolerization strategy that incorporates IL-12 DNA aptamers and the cholera toxin B subunit (CTB) immunomodulator for enhanced autoantigen mediated suppression of type1 diabetes. The efficacy of this combinatorial vaccination strategy will be assessed by analysis of insulitis and hyperglycemia progression in non-obese diabetic (NOD) mice after oral inoculation with aptamers that bind IL-12 or its receptor (IL-12R), and edible plant produced CTB-insulin (INS) fusion protein. Mechanisms underlying IL-12/R aptamer and CTB-INS enhancement of immunological tolerance in immunized mice will be clarified by flow cytometric analysis of Peyer’s patches, mesenteric lymph node, and pancreatic dendritic cell populations and by ELISA quantification of DC intracellular IL-12 and IL-10 cytokines. The effects of aptamer and CTB-INS on stimulation of regulatory T cell expansion and activation will be determined by flow cytometric analysis of CD4+ T cell FOXP3, GITR and CTLA-4 marker protein induction and by ELISA quantification of autoantigen challenged T cell secreted IL-10 and TGF-β. Determination of the fundamental mechanisms underlying aptamer and CTB enhancement of autoantigen mediated immunological tolerance will establish a basis for oligo-array and RNAi identification of DC and Treg genes involved in coordination of aptamer and immunomodulator enhanced diabetes suppression. The proposed experiments will provide a foundation for development of coordinated multicomponent immunomodulation strategies for restoration of immunological homeostasis in patients with type 1 diabetes and other chronic organ specific inflammatory diseases that contribute to increased mortality especially in under represented populations with disparities in health outcomes. Collaborators, Dr Jeeva Vivekananda, USAF Research Laboratory, Brooks Base, San Antonio, TX. (06/2008 - 07/2009)
  • NIH R21 Proposal: Novel Immunotherapy Strategies for Type 1 Diabetes, In response to PA-03-107, Submitted 6/14/07, Budget $441,375. for 3 yr. While single dimensional therapeutic approaches may effect short term autoimmune disease suppression, they have not been shown to provide effective and durable intervention for Type 1 diabetes. Thus, an integrated approach through incorporation of multiple interventional modalities may provide more effective and sustainable therapeutic intervention. To test this hypothesis, we propose to couple specific aptamers that inhibt inflammatory cytokines with adjuvant linked autoantigens that stimulate reduced diabetes insulitis and hyperglycemia to halt or prevent pancreatic islet beta cell apoptosis. To to bring this novel multicomponent immunosuppression strategy to the clinic, mechanisms underlying aptamer and adjuvant contributions to autoantigen mediated immunological tolerance must be clarified. Toward achievement of this goal, anti-cytokine aptamer and cholera toxin B subunit-proinsulin fusion protein (CTB-INS) contributions to the modulation of dendritic cell maturation, and expansion and activation of regulatory T lymphocyte populations will be examined in the clinically relevant NOD mouse. To reduce immunity to carrier proteins, a heterologous vaccinia virus prime-boost oral inoculation strategy will be used in Aim 1, to enhance CTB-INS suppression of islet inflammation and hyperglycemia. In Aims 2 and 3, aptamer and CTB contributions to insulin mediated immunotolerization will be examined by flow cytometric and ELISA analysis of dendritic cell maturation and cytokine biosynthesis in inoculated NOD mouse pancreatic and gut-associated lymphoid tissues. Expansion and activation of regulatory T cell populations stimulated by aptamers and CTB-INS treatment will be confirmed by flow cytometric analysis of FOXP3, GITR and CTLA-4 markers, and by ELISA quantification of regulatory T cell cytokine secretion in inoculated mouse lymphoid tissues. Examination of aptamer and adjuvant enhanced autoantigen suppression of T1D will establish the efficacy of multicomponent interventional modalities for immune suppression of T1D and provide a basis for identification of genes involved in aptamer and adjuvant enhancement of autoantigen mediated peripheral tolerance. Reaching these goals will be a major step toward providing safer, more effective and affordable immuno-tolerization strategies for restoration of immunological homeostasis in racial and ethnic groups where diabetes and chronic inflammatory diseases generate significant health care disparities. (06/2007 - 06/2009)
  • Aptamer Prevention of Acute Rotavirus Gastroenteritis: Submitted to the Gates Foundation, May 30, 2008, Budget: $100,000 for 1 yr. Rotaviruses (RV) are the leading etiologic agents of severe diarrheal disease in infants and young children responsible for over 600,000 annual deaths worldwide (Parashar et al., 2006). The time of greatest vulnerability to RV infection is during  infancy to 3-5 yr of age, a time when the immune system is not fully formed and maternal breast milk protection has disappeared from the weaned infant. To protect the infant during this vulnerable time we propose a novel approach, oral inoculation with ssDNA aptamers specific for the  rotavirus toxin NSP4  RV spike  and alpha-integrin receptor proteins. This strategy will allow both inactivation of the toxin and blockage of alpha integrin intestinal epithelial cell receptors thereby preventing virus attachment and protecting against the onset of diarrhea.   (05/2008 - 05/2009)
  • NIH R01 Proposal: Immunostimulation of Autoantigen Mediated Tolerance, NIH Application number 1 R01 DK082747-01, Submitted 2/06/08, Budget $750,000. for 3 yr. Single therapeutic strategies can provide short term suppression of organ specific autoimmunity. However, few individual therapies demonstrate effective and durable disease intervention. Combinatorial therapeutic strategies incorporating immunostimulatory molecules that enhance autoantigen mediated immunological tolerance may provide more effective and sustainable autoimmune disease prevention. Fusion proteins containing the immunostimulatory cholera toxin B subunit (CTB) molecule linked to pancreatic autoantigens such as insulin or GAD can greatly enhance autoantigen mediated immune suppression of Type 1 diabetes. To harness this promising immunotolerization strategy for safe and effective interventional therapy, mechanisms underlying CTB stimulation of immunotolerance must be elucidated. To achieve this goal, recent hypotheses that suggest CTB contributes to enhancement of immunological tolerance by stimulating immature dendritic cell (DC) suppression of inflammatory cytokines responsible for autoreactive CD4+ T cell development will be explored in the non-obese diabetic (NOD) mouse preclinical animal model. Alternatively, CTB-INS contributions to expansion and activation of regulatory T cell subsets leading to inhibition of DC maturation will be quantified in a parallel set of flow cytometric and ELISA experiments. In addition to establishing a basis for oligo array, rtPCR and siRNA experiments for identification of genes involved in the regulaton of CTB-INS DC receptor binding and immune suppression in diabetic mice, short term translational benefits from this study will include immunomodulator-autoantigen supplementation or replacement of nonspecific immunosuppressants, anti-inflammatory agents and surgical interventional therapies that can increase patient vulnerability to infection. An improved understanding of CTB-INS contributions to the induction of regulatory T cell populations and their activation for suppression of autoimmunity will permit development of alternative immunomodulator-autoantigen combinations for more effective interventional therapy against the progression of type1 diabetes and in the longer term other Th1 lymphocyte mediated chronic organ specific autoimmune diseases        (02/2008)