Grant of the Month 2019

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.

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PI: Xinyan Tracy Cui

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

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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

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PI: Fabrisia Ambrosio

Co-PI: Philip LeDuc

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

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Author: Zamora R, Barclay D, Yin J, Alonso EM, Leonis MA, Mi Q, Billiar TR, Simmons RL, Squires RH, Vodovotz Y

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PI: Ron Poropatich

PI (Pitt): Michael Pinsky

PI (CMU): Artur Dubrawski

Title: TRAuma Care In a Rucksack: TRACIR

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PI: Pamela Moalli

Co-PI: Steven Abramowitch

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

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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.

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PI: Marc Simon

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

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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.

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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.

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