PI: William Wagner
Co-PI: John Alcorn, Stephen Badylak, Louis Falo, William Federspiel, Neeraj Gandhi, Eric Lagasse, Steven Little, Alan Wells, and Cecilia Yates
PI: William Federspiel / Ryan Orizondo
Title: Omniphobic coating of extracorporeal life support systems for improved thromboresistance (Subaward)
PI: Louis Falo
Title: Engineering the Skin Immune System to Induce Systemic Immune Responses
Description: The skin functions as a potent immune organ, rendering the readily accessible cutaneous microenvironment an attractive target that can be locally engineered to induce and regulate systemic immune responses. Increasing age is associated with changes in immune function (immunosenescence) that result in increased susceptibility to diseases and poor vaccine responses in older adults. This proposal is designed to bring together very recent and significant advances in dermatology and skin biology to address critical problems in human health. Here, we specifically focus on the skin microenvironment and strategies for cutaneous immunomodulation. The overall approach is to utilize a clinically applicable dissolvable microneedle array delivery platform we have developed to locally engineer the highly adaptive and immunoresponsive skin microenvironment. Specifically, we propose to modulate local immune regulatory circuits in the skin to enable the induction and regulation of systemic immune responses. The studies we propose will investigate the effect of locally delivered immune modulators on the mechanisms underlying cutaneous immune regulation in young and aged skin. Importantly, our studies include translational studies using living human skin to enable the rapid advancement of novel cutaneous immunomodulation strategies into clinical trials. The proposed studies will result in a better understanding of skin immunobiology specifically relevant to the development of safe and predictable skin immunoengineering strategies to regulate systemic immune responses across the lifespan.
PI: Alejandro Almarza
Co-PI: Juan Taboas
Title: Polymer Scaffolds for Mandibular Condyle Cartilage Regeneration
PI: George Michalopoulos
Title: Inhibition of EGF Receptor Prevents and Reverses Non-Alcoholic Fatty Liver Disease
PI: William R. Wagner
Title: Support for Proof-of-Concept Studies in Regenerative Medicine
Description: This proposal provides support for proof-of concept studies for advancing the state-of-the-art in regenerative medicine. Successful studies will be positioned to compete for advanced studies with funding from Federal agencies. The proposal includes projects involving both clinical and academic researchers all of whom are active in the growing field of Regenerative Medicine.
PIs: David Vorp
Title: Preclinical Optimization and Design for Manufacturability of Immunoregulatory Tissue-Engineered Vascular Graft
PIs: Piervincenzo Rizzo
Co-PIs: Samuel Dickerson, Ian Sigal, Ian Conner, and Robert Handzel
Title: Managing Glaucoma in the Digital Age: A New Tonometer to Connect Patients to their Caregivers
PIs: D. Lansing Taylor, Jaideep Behari, and Alejandro Soto-Guttierrez
Title: A Vascularized Patient-Derived iPSC Liver Acinus Microphysiological System as an Innovative Precision Medicine Platform for Optimizing Clinical Trial Design for Nonalcoholic Fatty Liver Disease
PIs: David H. Kohn, William V. Giannobile, David J. Mooney, Charles Sfeir, and William R. Wagner
Title: Michigan-Pittsburgh-Wyss Regenerative Medicine Resource Center: Advancing Dental, Oral, and Craniofacial Regeneration to Clinical Trial Initiation
PI: George Gittes
Title: Alpha Cells Conversion to Beta Cells in Non-Human Primates
Description: An ideal solution to the treatment or cure of type 1 diabetes mellitus would be the formation of new functioning β-cells from the patient’s own tissues that are not attacked by the autoimmunity, thereby avoiding the need for any immunosuppression. Abundant recent data have suggested that α-cells are a viable potential source for endogenous transdifferentiation into β-cells. Here, we describe a pancreatic intraductal viral delivery system in the mouse, wherein a single infusion of an adeno-associated virus (AAV), carrying a pdx1/mafA expression vector, is given to a toxin-induced (alloxan) diabetic mouse. This AAV gene therapy induced robust and durable α-cell transdifferentiation into β-cell-like cells through neogenesis, with recovery of over 60% of the β-cell mass within 4 weeks, and with persistent, durable euglycemia. Serendipitously, when this β-cell-like cell neogenesis was similarly induced in the autoimmune NOD mouse model, the mice became euglycemic for 4 months or more, without any additional therapy or immunosuppression. To our knowledge, no clinically applicable β-cell replacement therapy in NOD mice has been successful without immunosuppression. We suspect that the neogenic β-cell-like cells may not be attacked by the autoimmunity because they are “imperfect” β-cells by RNA-seq analysis. Since pancreatic duct injection is routinely performed in humans as a relatively simple, non-surgical procedure, and since numerous viral gene therapy trials are currently ongoing for several diseases, we feel that our approach may be rapidly translatable to humans with type 1 diabetes mellitus. In this proposal, we will perform important proof-of-principle studies in non-human primates as last steps in preparation for human gene therapy clinical trials. The primate pancreas has a very different texture and consistency than the mouse pancreas (and is very similar to the human pancreas). Thus, the mechanics of the viral delivery will likely require substantial alterations. In addition, a glucagon promoter is preferable to the CMV promoter for expression of pdx1 and mafA, so we will strive to develop and optimize a glucagon promoter vector that is effective in primates. Further studies will investigate this pancreatic ductal infusion approach in the context of AAV neutralizing antibodies. We will also perform detailed analyses of the new β-cell-like cells, including physiology, gene expression phenotype, and anatomy. In summary, we feel that the proposed studies, if successful, should position us well in preparation for clinical trials in humans with type 1 diabetes mellitus.
PI: Fabrisia Ambrosio
PI: Thomas Rando
Title: Alliance for Regenerative Rehabilitation Research & Training (AR3T)
