Grant of the Month

PI: Donghun Shin

Title: Delineating the molecular mechanisms of hepatocyte-to-cholangiocyte reprogramming Read More

PI: Sruti Shiva

Co-PI: Anthony J. Molina

Title: The relationship between blood based bioenergetics and muscle function, mobility, and aging Read More

PI: Kang Kim

Title: Super Resolution Ultrasound Imaging of Vasa Vasorum to Characterize the Progression of Atherosclerotic Plaques and Predict Rupture Vulnerability Read More

PI: Jonathan Vande Geest

Title: Preclinical Assessment of a Compliance Matched Biopolymer Vascular Graft Read More

PIs: Pamela Moalli, Kyle Orwig, and Caroline Gargett

Title: Vaginal Stem Cells: The Missing Link in Vaginal Reconstruction Read More

Program Director: James Luketich

Co-PDs: Julie Phillippi and David Vorp

Title: Cardiothoracic Surgery Research Training Program Read More

PI: Andrew Duncan

Title: Mechanisms of Liver Regeneration Induced by Acetaminophen Toxicity

Description: Liver disorders affect 30 million people in the United States and are the country’s 10th leading cause of death. To improve liver disease treatments, a better understanding of hepatocyte biology is required. The liver contains diploid and polyploid hepatocytes, with polyploids comprising nearly 50% adult human and 90% adult mouse hepatocytes. The functional differences between diploid and polyploid hepatocytes are poorly understood. We previously demonstrated that diploid hepatocytes facilitate rapid liver regeneration, but it remains unknown how diploid and polyploid hepatocytes respond to drug-induced injury. Acetaminophen (APAP) is a common analgesic that can cause acute liver injury, resulting in liver failure and death when taken in excess. When APAP overdose causes extensive centrilobular hepatocyte death, the liver undergoes compensatory proliferation and recovers if the ratio of necrosis to regeneration is low. To investigate the role diploid and polyploid hepatocytes in vivo, we utilize E2f7 and E2f8 liver-specific knockout mice (LKO) where E2f7 and E2f8 are deleted during postnatal development; these mice are functionally normal through 6-9 months of age but are depleted of polyploid hepatocytes (LKO livers are >70% diploid). Preliminary studies indicate that LKO mice enriched with diploid hepatocytes are less damaged and recover faster from APAP injury than wild-type (WT) mice enriched with polyploid hepatocytes. The Grantee shall investigate mechanisms of liver injury and regeneration during APAP-induced liver injury and failure. This project shall determine ploidy-dependent and ploidy-independent mechanisms of liver repair and regeneration following APAP overdose. Read More

PI: Alisse Hauspurg

Co-I: Ramakrishna Mukkamala, Sanjeev Shroff, and Aman Mahajan

Title: Development of a smartphone-based device to detect fluid overload among postpartum women with hypertensive disorders of pregnancy Read More

PI: Mo Ebrahimkhani and Samira Kiani

Title: Collaborative Research: RECODE: Directed Differentiation of Human Liver Organoids via Computational Analysis and Engineering of Gene Regulatory Networks Read More

PI: Kacey Marra

Title: Development of an Implantable Medical Device for Human Extremity Nerve Injuries Read More

PI: William Wagner

Co-PI: John Alcorn, Stephen Badylak,  Louis Falo, William Federspiel, Neeraj Gandhi, Eric Lagasse, Steven Little, Alan Wells, and Cecilia Yates Read More

PI: William Federspiel / Ryan Orizondo

Title: Omniphobic coating of extracorporeal life support systems for improved thromboresistance (Subaward) Read More

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. Read More

PI: Alejandro Almarza

Co-PI: Juan Taboas

Title: Polymer Scaffolds for Mandibular Condyle Cartilage Regeneration Read More

PI: George Michalopoulos

Title: Inhibition of EGF Receptor Prevents and Reverses Non-Alcoholic Fatty Liver Disease Read More

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. Read More

PIs: David Vorp

Title: Preclinical Optimization and Design for Manufacturability of Immunoregulatory Tissue-Engineered Vascular Graft Read More

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 Read More

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 Read More

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 Read More

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. Read More

PI: Fabrisia Ambrosio

PI: Thomas Rando

Title: Alliance for Regenerative Rehabilitation Research & Training (AR3T) Read More

PI: David Vorp

Title: The Role of Fibrinolysis in Tissue Engineered Vascular Grafts for Aged Individuals Read More

PI: Anita McElroy

Co-PIs: Paul Duprex and Alan Wells

Title: SARS-CoV-2 clinical and community serosurveillance Read More

PI: Takashi Kozai

Title: CAREER: Uncovering the Impact of Traditional and Novel Chronic Stimulation Modalities on Neural Excitability and Native Neuronal Network Function Read More

PI: Cecelia Yates

Title: FibroKine™ biomimetic peptides as potential targeted therapeutic treatment of pulmonary fibrosis Read More

PI: Stephen Badylak

Title: REPAIR: Regenerative Electronic Patch through Advanced Intelligent Regulation Read More

PI: Radosveta Koldamova

Co-PI: Fabrisia Ambrosio

Title: Physical exercise and blood-brain communication: Exosomes, Klotho and the Choroid Plexus Read More

PI: Jeffrey Gross

Title: Elucidating the Molecular Underpinnings of Endogenous RPE Regeneration

Description: Diseases resulting in degeneration of the retinal pigment epithelium (RPE) are among the leading causes of blindness worldwide and no therapy exists that can replace RPE or restore lost vision. Age-related macular degeneration (AMD) is one such disease and is the third leading cause of blindness in the world. While there are some effective treatments for exudative (wet) AMD, ~90% of AMD cases are atrophic (dry) and these are currently untreatable. Transplantation of stem-cell derived RPE has emerged as a possibility for treating geographic atrophy and clinical trials are underway. However, little is known about the fate of transplanted RPE and whether their survival and integration can be improved. An intriguing alternative approach to treating AMD and other RPE diseases is to develop therapies focused on stimulating endogenous RPE regeneration. For this to be possible, we must first gain a deeper understanding of the mechanisms underlying RPE regeneration. In mammals, RPE regeneration is extremely limited and, in some contexts, RPE cells overproliferate after injury, such as during proliferative vitreoretinopathy, where proliferative RPE cells invade the subretinal space and lead to blindness. Recently, a subpopulation of quiescent human RPE stem cells was identified that can be induced to proliferate in vitro and differentiate into RPE or mesenchymal cell types, suggesting that the human RPE contains a population of cells that could be induced to regenerate. Despite these studies, little is known about the process by which RPE cells respond to injury to elicit a regenerative, rather than pathological, response. Indeed, no studies have demonstrated regeneration of a functional RPE monolayer following severe RPE damage in any model system. The development of such a model is a critical first step to acquiring a deeper understanding of the molecular mechanisms underlying RPE regeneration. This knowledge gap is a major barrier to developing effective strategies to restore RPE lost to disease or injury and is the focus of our proposal. We developed a transgenic zebrafish model to study RPE injury and regeneration and demonstrate that the zebrafish RPE regenerates after severe injury. We further demonstrate i) that RPE regeneration involves a robust proliferative response during which proliferative cells move to the injury site and differentiate into RPE, ii) that the source of regenerated cells is likely uninjured peripheral RPE, iii) using this system, we can identify the molecular underpinnings of the regenerative response, and iv) the innate immune system plays a critical role in RPE regeneration. Experiments in this proposal build off of these strong preliminary data to test the hypothesis that RPE regeneration is affected by a population of injury-activated resident RPE cells that proliferate upon injury and regenerate lost RPE tissue. Understanding how injury-responsive RPE cells proliferate in vivo and the signals/pathways active during the injury response holds significant promise to identify strategies to stimulate or reactivate this ability in the human eye, which would be transformational for treating AMD and other diseases that affect the RPE. Read More

PI: Partha Roy

Co-PI: Michael Lotze

Title: Profilin 1 as a Novel Target in Patients with Renal Cancer

Description: Malignant tumors of the kidney account in 2018 for 63,000 new cases and 15,000 deaths in the U.S. The most common subtype, clear cell renal cell carcinoma (ccRCC), is found in >75% of cases. Approximately 20%-30% of patients have metastasis at the time of diagnosis. About one-third of patients following initial treatment will develop either local recurrence and/or distant metastasis. The five-year survival of patients with advanced ccRCC is still only 10%. Drugs targeted to block expansion of vascular network in the tumor (anti-angiogenic therapy, a common treatment for ccRCC patients) is only effective initially, but in most patients the disease continues to progress due to drug resistance. Immunotherapy, a mode of treatment that hijacks the patient’s immune system to fight back the cancer, has shown significant promise, at least in some patients. Therefore, a more in-depth molecular understanding of the pathogenesis and progression of the exuberant vascularization of ccRCC, coupled with understanding of the immunologic sequelae, will lead to new integrated therapies. In this proposed study, we will address several major FY18 KCRP areas of emphasis including targeted therapies, microenvironment and immunology, and prognosis of RCC. Specifically, we will investigate whether and how profilin1 (Pfn1), a molecule elevated primarily in blood vessels in ccRCC and that correlates with advanced stage of tumor and poor prognosis of patients (a) contributes to altering tumor microenvironment and disease progression, and (b) predicts the response of RCC patients to immunotherapy. We will then explore whether efforts to target Pfn1 function through novel small molecules are effective in retarding disease progression in preclinical models. From these studies we will identify Pfn1 as a regulator of disease progression as well as a prognostic marker for predicting therapeutic response of RCC patients. A successful proof-of-concept demonstration of the efficacy of Pfn1-targeting chemical tools in retarding angiogenesis-dependent disease progression will establish the conceptual basis for a path forward toward a new direction of Pfn1-targeted therapy for patients with ccRCC. If successful, these small molecules can be further advanced through medicinal chemistry to generate next-generation drugs for RCC, demonstrating that our studies have translational potential in the future. Read More

PI: Xinyan Tracy Cui

Title: Optimization and Delivery of Bioactive Coating for High Yield and Stable Neural Recording Read More

Multi-PIs: Hang Lin and Michael Gold

Co-I: Douglas Weber

Title: Joint Pain on a Chip: Mechanistic Analysis Therapeutic Targets and an Empirical Strategy for Personalized Pain Management Read More

PI: Fabrisia Ambrosio

Co-PI: Philip LeDuc

Co-Investigators: Antonio D’Amore, Aaron Barchowsky, and Claudette St. Croix Read More

PI: Ryad Benosman

Co-PI: Feng Xiong

Title: FET: Small: Neuromorphic Spiking Neural Networks with Dynamic Graphene Synapses for Event-based Computation Read More

PI: Ron Poropatich

PI (Pitt): Michael Pinsky

PI (CMU): Artur Dubrawski

Title: TRAuma Care In a Rucksack: TRACIR Read More

PI: Pamela Moalli

Co-PI: Steven Abramowitch

Title: Overcoming Complications of Polypropylene Prolapse Meshes: Development of Novel Elastomeric Auxetic Devices Read More

PI: Michael Boninger

Title: A Biomimetic Approach towards a Dexterous Neuroprosthesis

Description: Cervical spinal cord injury results in the loss of arm and hand function, which significantly limits independence and results in costs over the person’s lifespan. A brain-computer interface (BCI) can be used to bypass the injured tissue to enable control of a robotic arm and to provide somatosensory feedback. Two primary limitations of current state-of-the-art BCIs for arm and hand control are: (1) the inability to control the forces exerted by the prosthetic hand and (2) the lack of somatosensory feedback from the hand. In the proposed study, we seek to considerably improve dexterous control of prosthetic limbs by implementing decoding strategies that enable the user to not only control the movements of the arm and hand, but also the forces transmitted through the hand. We anticipate that our biomimetic approach to decoding will yield intuitive, dexterous control of the prosthetic hand. Tactile sensations will be conveyed to the user through intracortical microstimulation (ICMS) of somatosensory cortex. The spatiotemporal patterns of stimulation will be based on our basic scientific understanding of how tactile information is encoded in somatosensory cortex, which we expect will result in more natural and intuitive sensations. In order to achieve our goal of developing a dexterous neuroprosthesis, we have brought together a team with human BCI experience from the University of Pittsburgh along with the basic science expertise at both Pitt and the University of Chicago. We will collaborate with experts in implantable neurotechnology (Blackrock Microsystems) and robotics (The Biorobotics Institute) to ensure that the device hardware allows us to take a biomimetic approach for control and feedback with an eye toward clinical translation. A total of 4 participants will be tested in a multisite study to accomplish the following three specific aims. Aim 1: Evoke natural and intuitive tactile sensations through ICMS of somatosensory cortex. We expect that biomimetic ICMS will evoke sensations that more closely resemble everyday tactile sensations and intuitively convey information about contacted objects than does standard fixed-frequency ICMS. Aim 2: Derive kinematic and kinetic signals from motor cortex for hand control. We will assess the degree to which motor cortical neurons encode forces exerted on objects. Based on these observations, we will develop hybrid decoders that enable controlling both the movement and force using a synergy-based approach. Aim 3: Demonstrate improved arm and hand function with a biomimetic sensorimotor BCI that combines the sensory feedback developed in Aim 1 with the hybrid decoding developed in Aim 2. A battery of functional assessments will be used including novel metrics designed specifically for sensorimotor prosthetics along with well-established tests identified in the NIH Common Data Elements. We anticipate that subjects will substantially improve their dexterity using a biomimetic BCI as compared to non-biomimetic BCIs or BCIs without somatosensory feedback. Read More

PI: Marc Simon

Title: A Phase II Trial of Metformin for Pulmonary Hypertension in Heart Failure with Preserved Ejection Fraction Read More

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. Read More

PI: Michael Boninger

Title: A Biomimetic Approach Towards a Dexterous Neuroprosthesis

Description: Cervical spinal cord injury results in the loss of arm and hand function, which significantly limits independence and results in costs over the person’s lifespan. A brain-computer interface (BCI) can be used to bypass the injured tissue to enable control of a robotic arm and to provide somatosensory feedback. Two primary limitations of current state-of-the-art BCIs for arm and hand control are: (1) the inability to control the forces exerted by the prosthetic hand and (2) the lack of somatosensory feedback from the hand. In the proposed study, we seek to considerably improve dexterous control of prosthetic limbs by implementing decoding strategies that enable the user to not only control the movements of the arm and hand, but also the forces transmitted through the hand. We anticipate that our biomimetic approach to decoding will yield intuitive, dexterous control of the prosthetic hand. Tactile sensations will be conveyed to the user through intracortical microstimulation (ICMS) of somatosensory cortex. The spatiotemporal patterns of stimulation will be based on our basic scientific understanding of how tactile information is encoded in somatosensory cortex, which we expect will result in more natural and intuitive sensations. In order to achieve our goal of developing a dexterous neuroprosthesis, we have brought together a team with human BCI experience from the University of Pittsburgh along with the basic science expertise at both Pitt and the University of Chicago. We will collaborate with experts in implantable neurotechnology (Blackrock Microsystems) and robotics (The Biorobotics Institute) to ensure that the device hardware allows us to take a biomimetic approach for control and feedback with an eye toward clinical translation. A total of 4 participants will be tested in a multisite study to accomplish the following three specific aims. Aim 1: Evoke natural and intuitive tactile sensations through ICMS of somatosensory cortex. We expect that biomimetic ICMS will evoke sensations that more closely resemble everyday tactile sensations and intuitively convey information about contacted objects than does standard fixed-frequency ICMS. Aim 2: Derive kinematic and kinetic signals from motor cortex for hand control. We will assess the degree to which motor cortical neurons encode forces exerted on objects. Based on these observations, we will develop hybrid decoders that enable controlling both the movement and force using a synergy-based approach. Aim 3: Demonstrate improved arm and hand function with a biomimetic sensorimotor BCI that combines the sensory feedback developed in Aim 1 with the hybrid decoding developed in Aim 2. A battery of functional assessments will be used including novel metrics designed specifically for sensorimotor prosthetics along with well-established tests identified in the NIH Common Data Elements. We anticipate that subjects will substantially improve their dexterity using a biomimetic BCI as compared to non-biomimetic BCIs or BCIs without somatosensory feedback. Read More