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
Grant of the Month
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2020 | November 25, 2020
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2020 | October 26, 2020
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
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2020 | September 30, 2020
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
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2020 | August 27, 2020
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 2020 | July 28, 2020
PI: Fabrisia Ambrosio
PI: Thomas Rando
Title: Alliance for Regenerative Rehabilitation Research & Training (AR3T)
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2020 | June 24, 2020
PI: David Vorp
Title: The Role of Fibrinolysis in Tissue Engineered Vascular Grafts for Aged Individuals
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2020 | May 28, 2020
PI: Anita McElroy
Co-PIs: Paul Duprex and Alan Wells
Title: SARS-CoV-2 clinical and community serosurveillance
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2020 | May 26, 2020
PI: Takashi Kozai
Title: CAREER: Uncovering the Impact of Traditional and Novel Chronic Stimulation Modalities on Neural Excitability and Native Neuronal Network Function
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2020 | March 31, 2020
PI: Cecelia Yates
Title: FibroKine™ biomimetic peptides as potential targeted therapeutic treatment of pulmonary fibrosis
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2020 | February 26, 2020
PI: Stephen Badylak
Title: REPAIR: Regenerative Electronic Patch through Advanced Intelligent Regulation
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2020 | January 28, 2020
PI: Radosveta Koldamova
Co-PI: Fabrisia Ambrosio
Title: Physical exercise and blood-brain communication: Exosomes, Klotho and the Choroid Plexus
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2019 | December 19, 2019
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.
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2019 | November 25, 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.
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2019 | October 22, 2019
PI: Xinyan Tracy Cui
Title: Optimization and Delivery of Bioactive Coating for High Yield and Stable Neural Recording
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2019 | September 27, 2019
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
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2019 | August 28, 2019
PI: Fabrisia Ambrosio
Co-PI: Philip LeDuc
Co-Investigators: Antonio D’Amore, Aaron Barchowsky, and Claudette St. Croix
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2019 | July 30, 2019
PI: Ryad Benosman
Co-PI: Feng Xiong
Title: FET: Small: Neuromorphic Spiking Neural Networks with Dynamic Graphene Synapses for Event-based Computation
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.
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2018 | January 16, 2019
PI: Moni K. Datta
Co-PI: Prashant Kumta and Robert Kormos
Title: Novel Aptamer-Based Biosensor Platforms for Detection of Cardiomyopathy Conditions
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2018 | November 30, 2018
PI: Piervincenzo Rizzo (Principal Investigator), Ian Conner (Co-Principal Investigator), Samuel Dickerson (Co-Principal Investigator)
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2018 | October 26, 2018
PI: William R, Wagner, PhD Co-investigator, Donald Taylor, PhD, MBA Co-investigator
Title: Philadelphia-Pittsburgh Pediatric Medical Device Consortium
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2018 | September 28, 2018
PI: J. Peter Rubin
Title: Integrated Clilnical and Research Systems for Diabetic Foot Wound Care
Description: Diabetes is a common, complex, and costly disease affecting 9.4% (30.3 millions) of Americans. It remains the 7th leading cause of death in the United States, contributing to over 250,000 deaths annually. Diabetic foot ulcers (DFU) are the most frequently recognized complication in diabetics with an incidence of 6% in the diabetic global population, 6% among Medicare diabetic beneficiaries, 5% among diabetic U.S. veterans and a lifetime incidence of foot ulcers between 19% and 34% in diabetics. The natural history of a diabetes-related foot ulcer is devastating. More than half of ulcers become infected and approximately 20% of moderate or severe diabetic foot infections lead to amputation. Mortality after diabetes-related amputations is greater than 70% at 5 years for all patients with diabetes, which is 2.5 times higher than in diabetic patients without a foot ulcer. This proposal is designed to establish a clinical research unit (CRU) at the University of Pittsburgh Medical Center that integrates high quality care delivery seamlessly with outstanding clinical research. The CRU will then be a participating site in the NIH consortium studying biomarkers for diabetic foot ulcer healing. Our central hypothesis is that we can address the major challenges of diabetic foot ulcer clinical research through the seamless integration of wound center clinical operations with research operations. Our specific aims are: Aim 1: Establish a unified recruiting and retention system integrated with the clinical operations of our wound care service line, and linked to our EPIC scheduling system and electronic medical record (EMR). Aim 2: Establish integrated research quality systems, linked to highly standardized clinical pathways, and supported by a wound Informatics and Data Core connecting our 8 wound care centers.
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2018 | August 28, 2018
PI: Joseph Glorioso and Gary Cohen, PhD
Title: Cancer Vaccine for Melanoma
Description: Drs. Glorioso and Cohen will share a two-year ACGT grant to support a study to develop a cancer vaccine for melanoma. Their research builds on previously successful results using a tumor-targeted, actively replicating herpes virus to infiltrate cancers and stimulate an immune system assault. Dr. Glorioso calls the methodology a “heat-seeking missile that targets metastatic cancer for destruction.” The treatment doesn’t stop there. Once the cancer is eliminated, the vaccine inserts an immunity barrier to protect against recurrence. Melanoma is among the most deadly cancers and this treatment offers new hope.
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2018 | July 30, 2018
PI: Shilpa Sant
Title: Three-dimensional organoid models to study breast cancer progression
Description: Approximately 20% of breast cancers detected through mammography are pre-invasive Ductal Carcinoma in situ (DCIS). If left untreated, approximately 20-50% of DCIS will progress to more deadly Invasive Ductal Carcinoma (IDC). No prognostic biomarkers can reliably predict the risk of progression from DCIS to IDC. Similar genomic profiles of matched pre-invasive DCIS and IDC suggests that the progression is not driven by genetic aberrations in DCIS cells, but microenvironmental factors, such as hypoxia and metabolic stress prevalent in DCIS, may drive the transition. We need innovative models to investigate how to halt steps of DCIS progression to invasive phenotypes and subsequent metastasis from the primary site. This proposal directly addresses this unmet need by developing a novel three-dimensional in vitro organoid model that recapitulates key hallmarks of DCIS to IDC progression: tumor-size induced hypoxia and metabolic stress, tumor heterogeneity and spontaneous emergence of migratory phenotype in the same parent cells without any additional stimulus. A tangible advantage of the proposed organoid models is the ability to precisely and reproducibly study how the hypoxic microenvironment induces tumor migration in real time and in isolation from non-tumor cells present in vivo, providing unique opportunity to define tumor-intrinsic mechanisms of DCIS to IDC progression. Our preliminary observations lead to central hypothesis that tumor size-induced hypoxia establishes a “hypoxic secretome”, which initiates the migratory phenotype; the hypoxic secretome then cooperate with intracellular signaling networks to independently maintain cell migration. We propose three independent but inter-related aims to link hypoxic secretome with the initiation, maintenance and spatial distribution of migratory phenotypes. Aim 1 will engineer size-controlled DCIS organoids (150-600 µm) with controlled hypoxic microenvironments to identify and examine how hypoxic secretome initiates migratory phenotype. We will combine experimental organoid models with time-lapse imaging and computational approaches to study organoid migration. Aim 2 will demonstrate that migratory cells can re-establish the secretome and maintain migratory phenotype independent of hypoxia. We will reconstruct an intracellular signaling network activated by the hypoxic secretome using microarray data. We will verify these gene expression signatures in sorted migratory and non-migratory cells, and validate them using secretome inhibition studies. Aim 3 will investigate, for the first time, the spatial distribution and origin of the migratory phenotype. We will use CRISPR-based gene knock-in (FP-labeling), automated image analyses, and a deep-learning algorithm to track and visualize the emergence of migratory phenotypes from the hypoxic core outward to the periphery or from the migratory front. The successful development of this 3D organoid model and completion of the proposed work will provide answers to two fundamental questions in the progression of invasive breast cancer: 1) What causes some DCIS cells to become migratory and develop into invasive tumors? 2) How and where does the migratory phenotype (IDC) emerge? The mechanistic understanding gained from these studies will improve diagnosis, lead to the development of treatment strategies to arrest invasion at the pre-malignant stage, and thus prevent patient overtreatment. It is straightforward to generalize our system to other tumor types, development of tumor/stromal co-culture, and drug screening.
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2018 | June 26, 2018
PI: Eric Lagasse
Title: A New Molecular Mechanism to Bioengineering a Liver
Description: Hepatocyte transplantation has many potential applications. Extensive animal experiments have shown that hepatocytes transplanted in the liver or at ectopic sites survive, function, and actively participate in the regenerative process. However, our understanding of hepatocyte engraftment and their remarkable proliferative and regenerative potential is limited, even if primary hepatocyte transplantation is at the doorstep of applications in the treatment of inherited and acquired human diseases. We previously made a serendipitous observation that normal hepatocytes transplanted in the peritoneal cavity of an animal with lethal liver disease migrate into the lymphatic system and engineer ectopic liver-like organoids that rescue an animal model from a fatal metabolic disorder. How hepatocytes enter the lymphatics and what molecular mechanism is responsible for the generation of ectopic mass is not known. We hypothesized that hepatocytes must borrow some of the molecular mechanism lymphocytes use to migrate into the lymphatics. Our interest will be to study ectopic cell transplantation and our central objective of our application is to translate a highly interesting observation, the generation of ectopic liver, to a potential clinical application for patients with liver diseases.
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2018 | May 24, 2018
PI: Dietrich Stephan
Title: LifeX
Description: The facility at 2124 Penn Ave. in Pittsburgh’s Strip District includes office and laboratory space where biotechnology companies can collaborate. In addition to the physical space, the LifeX platform brings together experts with proven track records of building new pharmaceuticals, medical devices, molecular diagnostics and population-health solutions to support entrepreneurs with deep industry knowledge. LifeX’s initial cohort of companies will focus on unmet health needs related to cancer, Alzheimer’s disease, multidrug-resistant bacterial infections, obesity and diabetes and rare genetic diseases.
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2018 | April 27, 2018
PI: Lee Fisher and Douglas J Weber
Title: Spinal root stimulation for restoration of function in lower-limb amputees
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2018 | March 28, 2018
PI: David Brienza
Title: Rehabilitation Engineering Research Center
Description: Researchers plan to spend the first few years of the grant improving or adding to existing standards, particularly related to cushion load-bearing performance, cushion durability, caster durability, and wheel rolling resistance, and the remaining few years applying those standards to different products. Ultimately, the researchers envision their work being used in several ways, including helping funding sources make reimbursement decisions, and clinicians, providers, and users make product decisions.
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2018 | February 27, 2018
PI: Jonathan Vande Geest
Title: Preclinical assessment of a compliance matched biopolymer vascular graft
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2018 | January 25, 2018
PI: Mike Schneider, DC, PhD
Co-PI: Anthony Delitto, PhD
Description: The researchers will compare spinal manipulation and supported self-management to usual medical care, which includes prescription medications for the care of acute lower back pain in adult patients at increased risk of becoming chronic.
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2017 | December 15, 2017
PI: Warren C. Ruder
Title: Creating Smart Biomaterials using Engineered Bacteria that Cooperatively Reprogram Mammalian Cells
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2017 | November 29, 2017
PI: Bryan Tillman
Co-I: Young Jae Chun
Title: An Organ Perfusion Stent as an Alternative to Surgery in Donor Organ Recovery
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2017 | October 30, 2017
PI: Lance Davidson
Title: Biomechanics of Morphogenesis
Description: Physical mechanical processes are central to the morphogenesis of embryos and their organs. The goal of this proposal is to apply a multi-scale analysis of the mechanics of convergent extension, identifying biomechanical mechanisms that establish passive tissue properties such as stiffness as well as active processes that generate forces of extension, regulate cell behaviors and tissue deformation, and how passive mechanics and active force generating processes are coordinated within the frog embryo. Studies outlined in this proposal will answer: (1) How are cell-scale structures and tissue mechanics are integrated during elongation? Early development is marked by dramatic changes in the mechanical properties of embryos. To understand how and why these properties change we test simple models of tissue mechanics based on synthetic closed-cell foams using bioengineering and biophysical methods to disrupt features from large scale architecture to the subcellular actomyosin-dependent cortex. (2) What single-cell mechanical processes contribute to convergent extension? We extend our analysis of cell behaviors to an unbiased approach that combines wide-field confocal microscopy with descriptive biomechanical analyses from the level of the cell, to the local neighborhood, to the strain fields of the entire embryo. Combining analyses of neural plate and paraxial somitic mesoderm we describe the dependence of these movements on planar polarity signaling. Using systems approaches we seek to test the dependencies of specific cell behaviors on both upstream signaling systems and their targeted downstream effectors. (3) How are tissue polarity cues transduced into polarized cell behaviors? We hypothesize that polarized cell behaviors and the oriented forces they generate are the result of cues produced by anisotropic strain. To test the roles of polarized intracellular factors and mechanical strain in organizing cell behaviors we use magnetogenetics and micro-scale tissue stretchers. Results from this project will complement ongoing efforts to identify the molecular regulators of morphogenesis by providing a conceptual framework developing new hypotheses of morphogenesis and bioengineering tools to test them. The significance of our work provides researchers a more complete understanding of the contribution of cell- and tissue-mechanics to development, to understand the role of tissue mechanics in oncogenesis, and to provide fundamental physical principles for future functional tissue engineers.
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2017 | September 29, 2017
PI: Rocky Tuan
Title: Tissue Chip Modeling of Synovial Joint Pathologies: Effects of Inflammation and Adipose-Mediated Diabetic Complications
By The McGowan Institute For Regenerative Medicine | Grant of the Month, Grant of the Month 2017 | August 30, 2017
PI: Julie Phillippi
Co-PI: Thomas Gleason, Marie Billaud, Vera Donnenberg, Stephen Badylak
Title: Matrix mediated vasa vasorum dysfunction in thoracic aortic disease