PI: Fabrisia Ambrosio
Co-PI: Philip LeDuc
Co-Investigators: Antonio D’Amore, Aaron Barchowsky, and Claudette St. Croix
Grant of the Month 2019
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2019 | August 28, 2019
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2019 | July 30, 2019
Author: Zamora R, Barclay D, Yin J, Alonso EM, Leonis MA, Mi Q, Billiar TR, Simmons RL, Squires RH, Vodovotz Y
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2019 | June 26, 2019
PI: Ron Poropatich
PI (Pitt): Michael Pinsky
PI (CMU): Artur Dubrawski
Title: TRAuma Care In a Rucksack: TRACIR
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2019 | May 29, 2019
PI: Pamela Moalli
Co-PI: Steven Abramowitch
Title: Overcoming Complications of Polypropylene Prolapse Meshes: Development of Novel Elastomeric Auxetic Devices
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2019 | April 29, 2019
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.
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2019 | April 10, 2019
PI: Marc Simon
Title: A Phase II Trial of Metformin for Pulmonary Hypertension in Heart Failure with Preserved Ejection Fraction
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2019 | February 26, 2019
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.
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2019 | January 28, 2019
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.