https://mirm-pitt.net/mirmold Tue, 26 Jul 2022 18:00:36 +0000 en-US 1.2 https://mirm-pitt.net/mirmold https://mirm-pitt.net/mirmold 1 144 https://wordpress.org/?v=6.0.1 https://mirm-pitt.net/mirmold/grant-of-the-month/grant-of-the-month-january-2022/ Fri, 28 Jan 2022 21:39:47 +0000 https://mirm-pitt.net/?p=172023 PI: Jonathan Vande Geest Title: Preclinical Assessment of a Compliance Matched Biopolymer Vascular Graft Description: There are approximately 250,000 coronary artery bypass graft (CABG) procedures performed annually to treat coronary heart disease (CHD) with graft failure rates reported to be as high as 42.8%. A major cause of graft failure in CABG has been attributed to graft compliance mismatch leading to subsequent intimal hyperplasia and graft thrombosis. The development of a compliance matched functional small diameter vascular graft will therefore significantly improve the treatment of those with CHD. Tissue engineering has shown promise in achieving some but not all of the required characteristics for a functional tissue engineered vascular graft (TEVG). A particularly challenging aspect in the development of a functional TEVG is the design of a fully biodegradable biopolymer graft that can be tuned to a desired compliance pre-implantation and subsequently maintain its compliance as it degrades and remodels in-vivo. As such there is a critical need to develop a compliance matched TEVG that remains compliance matched throughout the host remodeling process while also maintaining a functional endothelium. To meet this need we will develop and functionally assess a tropoelastin layered and endothelialized TEVG that is and remains compliance matched. We will utilize computational simulation to optimize the compliance of a biodegradable gelatin/tropoelastin layered TEVG that elutes TGFb2 in a controlled manner to promote early cell infiltration and late matrix deposition in our graft, thus stabilizing its compliance as our graft degrades. The overall working hypothesis of our research is that the intravital (in-vitro and in-vivo) compliance of our graft can be maintained by temporally controlling TGFb2 elution from a computationally optimized TEVG. We will test this hypothesis by completing the following Specific Aims. Aim 1 of our research project will assess if compliance and TGFb2 elution can maintain the compliance of our TEVG in-vivo using a rat aortic interpositional implantation model. Aim 2 of our proposed work will assess the function of our TEVG in a preclinical large animal (sheep carotid) implantation model. The proposed studies will establish a novel pre- and post-implantation compliance controlled fully biodegradable biopolymer TEVG with excellent patency, anti-thrombogenicity, vasoreactivity, and functional performance. Source: National Heart, Lung, and Blood Institute Term: December 15, 2021 – November 30, 2025 Amount: $658,593 (one year)]]> 172023 0 0 0 https://mirm-pitt.net/mirmold/grant-of-the-month/grant-of-the-month-february-2022/ Thu, 24 Feb 2022 20:09:59 +0000 https://mirm-pitt.net/?p=172118 PI: Kang Kim Title: Super Resolution Ultrasound Imaging of Vasa Vasorum to Characterize the Progression of Atherosclerotic Plaques and Predict Rupture Vulnerability Description: Acute coronary syndromes and strokes together constitute a leading cause of morbidity and mortality in the United States and Europe, approximately 80% of which are caused by atherosclerotic plaque (AP) rupture. Over the past decade, extensive efforts have been made to identify a rupture-prone AP. Among others, infiltration of dense neovascularization arising from vasa vasorum (VV) into the AP core plays a critical role in AP rupture. Postmortem studies revealed key involvement of VV in AP. However, a persistent lack of a noninvasive, high-resolution imaging tool to longitudinally assess abnormal microvascular expansion remains a critical barrier to adequate in-vivo investigation on how VV affects AP progression and contributes to eventual rupture. To address this dire unmet need, we propose an innovative transcutaneous super resolution ultrasound (SRU) imaging. The technology development in this project seeks to shift the current US imaging approach in identifying microvessels of AP from “intravascular” to a “fully noninvasive transcutaneous” imaging approach. This is only possible by achieving unprecedented high spatial resolution at large depth, breaking acoustic diffraction limit of the ultrasound frequency that governs spatial resolution. Our group has performed in-depth feasibility studies where SRU imaging successfully identified neomicrovessels in cholesterol-fed rabbit AP, evaluated against µCT and histology. Additionally, areas requiring further technical optimization were identified. Such technology developments and preliminary data thus far rigorously support our overarching hypothesis that enhanced and optimized SRU will accurately stage plaque progression and identify rupture- prone plaques by directly measuring VV changes with exquisite detail. To test the hypothesis, we will use a well-established, clinically relevant cholesterol-fed rabbit AP rupture model, which has shown the most similarity to human plaque pathology including VV neovascularization, to validate the novel SRU system to 1) Successfully quantify changes in vessel density and 2) Identify rupture-prone AP. To achieve these goals, we propose the following specific aims: 1) To develop enhanced SRU at high frequency using a commercial small animal imaging probe 2) To determine if VV changes estimated by SRU correlate with AP progression and are predictive of AP rupture. The immediate outcomes of the proposed work are an affordable noninvasive small animal SRU imaging tool and it’s validation on a clinically relevant rabbit AP model, which also can be used for other important small animal disease models, which are associated with microvessel abnormality such as cancer angiogenesis and kidney diseases to name a few. With proper adaptations into a clinical mid frequency probe and validation in clinical settings in future, this work will lead to our long-term translational goal to integrate SRU in a facile manner into the current clinical standard of carotid duplex sonography that has shown poor specificity to plaque vulnerability. This will help to effectively stratify patients at high risk of strokes and guide adequate intervention/treatment options for stroke prevention, exerting highly influential clinical impact. Source: National Heart, Lung, and Blood Institute Term: February 1, 2022 – January 31, 2026 Amount: $694,630 (one year)]]> 172118 0 0 0 https://mirm-pitt.net/mirmold/grant-of-the-month/grant-of-the-month-march-2022/ Fri, 25 Mar 2022 19:06:23 +0000 https://mirm-pitt.net/?p=172216 PI: Sruti Shiva Co-PI: Anthony J. Molina Title: The relationship between blood based bioenergetics and muscle function, mobility, and aging Description: As people age, they experience declining physical performance, which is associated with diminished quality of life, augmented health care costs, and is a strong predictor of morbidity and mortality. Thus, uncovering mechanisms that underlie age-associated mobility decline and identifying reliable biomarkers to predict this decline is imperative for the development of interventions to maintain physical ability with age. Mitochondria generate chemical energy to support homeostatic function of most cells in the body, and mitochondrial dysfunction is linked to age-associated decline in physical performance. This has been studied predominantly in skeletal muscle mitochondria since muscle function is central to physical ability. However, it is recognized that muscle function is not the sole determinant of mobility, and that input from other organ systems (cardiovascular and central nervous system) is also required. While age associated mitochondrial dysfunction has been observed across all organ systems, the contribution of this systemic bioenergetic dysfunction to age-associated mobility decline has not been assessed. The current study brings together two PIs with expertise in mitochondrial biology who have independently optimized and validated complementary assays (high resolution respirometery and Seahorse extracellular flux analysis) for the measurement of systemic bioenergetic function utilizing blood cells (platelets and peripheral blood mononuclear cells). Preliminary data using these assays show that blood cell mitochondrial function reflects bioenergetics of solid tissues (e.g. skeletal muscle, heart, lung, brain) and correlates with multiple measures of physical ability. However, it is unknown whether blood cell bioenergetics reflect skeletal muscle function or are predictive of mobility decline in older adults. The Study of Muscle, Mobility and Aging (SOMMA) is a multi-site longitudinal study of older adults (≥70 years; n=875). SOMMA focuses on the relationship between skeletal muscle mitochondria and mobility decline and will obtain skeletal muscle biopsies to measure mitochondrial function in all participants. Physical performance measures will at baseline and three years follow-up. The current proposal is an ancillary study that synergizes with SOMMA to add blood cell bioenergetic measurements in all SOMMA participants at baseline as well as at the three year follow up visit. Using these data, we will test whether blood cell bioenergetics are 1) reflective of skeletal muscle mass and function, 2) are associated with physical performance measures (400 m walk), and 3) are predictive of physical performance decline in older adults. Completion of this study will elucidate systemic mitochondrial changes that are associated with age-related physical decline, and potentially establish blood cell bioenergetics as a biomarker of systemic mitochondrial function that can be utilized as a surrogate for muscle biopsies, and as a predictor of mobility decline in the aging population. Source: National Institute on Aging Term: February 15, 2022 – November 30, 2026 Amount: $689,439 (one year)]]> 172216 0 0 0 https://mirm-pitt.net/mirmold/grant-of-the-month/grant-of-the-month-april-2022/ Wed, 27 Apr 2022 19:25:14 +0000 https://mirm-pitt.net/?p=172302 PI: Donghun Shin Title: Delineating the molecular mechanisms of hepatocyte-to-cholangiocyte reprogramming Description: Biliary epithelial cells (BECs; also called as cholangiocytes) that line the hepatic biliary tree control bile composition and flow. Injury to the BECs leads to cholestasis, which can progress to fibrosis, cirrhosis, and liver failure. Cholestatic liver diseases are associated with high morbidity and mortality; however, few effective therapies are available. In fact, liver transplantation is the only life-extending treatment for end-stage cholestatic liver diseases, but the shortage of donor livers makes this therapy extremely limited. In the injured liver with biliary damage, hepatocytes (HCs) can contribute to BECs to recover from the loss of BECs. Recent studies in mice have shown that HC-derived BECs contribute to the intrahepatic bile ducts, thereby restoring appropriate bile flow. Patients with biliary obstruction or cholangiopathies also exhibit biliary marker expression in HCs, suggesting their reprogramming into BECs. Thus, augmenting innate HC-to-BEC reprogramming in cholestatic liver diseases is an attractive therapeutic alternative to ameliorate cholestasis and subsequent cirrhosis. To develop such a therapy, it is crucial to better understand the molecular mechanisms underlying HC-to-BEC reprogramming. Furthermore, identifying small molecules that can augment the reprogramming should provide promising therapeutic drugs for patients with cholestatic liver diseases. Our long-term goal is to completely delineate the molecular mechanisms underlying HC-to-BEC reprogramming. As a first step in pursuit of that goal, the objective of this proposal is to determine the cellular and molecular characteristics of HC-to-BEC reprogramming-driven biliary regeneration in our two innovative zebrafish models and to elucidate how histone deacetylase 1 (hdac1) regulates HC-to-BEC reprogramming. Based on our preliminary data obtained from pharmacological and genetic studies, we hypothesize that Hdac1 inhibition promotes HC-to-BEC reprogramming by derepressing the Notch receptor gene notch2 and the signal transducer and activator of transcription 3 gene (stat3). We will test this hypothesis and accomplish the objective of this application by (1) elucidating the entire process of HC-to-BEC reprogramming-driven biliary regeneration in the two zebrafish models, in which complete absence of BECs is achieved and subsequently HCs convert to BECs, (2) determining the effects of Hdac1 inhibition on HC-to-BEC reprogramming in both zebrafish and mice, and (3) elucidating the molecular mechanisms by which Hdac1 inhibition promotes the reprogramming. The successful accomplishment of the proposed research will not only provide novel molecular mechanisms underlying HC-to-BEC reprogramming but also suggest HDAC1/2 inhibitors as promising therapeutic drugs to promote the reprogramming in patients with cholestatic liver diseases. Source: National Institute of Diabetes and Digestive and Kidney Diseases Term: April 1, 2022 – March 31, 2026 Amount: $514,858 (one year)]]> 172302 0 0 0 https://mirm-pitt.net/mirmold/grant-of-the-month/grant-of-the-month-may-2022/ Thu, 26 May 2022 20:46:57 +0000 https://mirm-pitt.net/?p=172465 PI: Eric Lagasse Title: Cell Therapy for Patients with End Stage Liver Disease Description: Obesity is a complex medical condition caused by dysregulation of systemic metabolism, excessive accumulation of body fat, insulin resistance and a variety of additional health issues.  Hepatocytes produce bile acids, which are recognized as key regulators of systemic metabolism, particularly systemic energy expenditure. In this pilot study, we propose experiments to transplant hepatocytes into lymph nodes of mice under fat-induced diet and compare to transplant of brown fat tissue into lymph nodes for an effective treatment of metabolic syndrome. Statement of Work: Cell-based therapy is a promising approach to generate hepatic functions in patients suffering from a variety of liver diseases. LyGenesis Inc. is a startup company focused on developing technology that enables a patient’s own lymph nodes to be used as bioreactors for hepatocyte transplantation and regeneration of an ectopic liver. The goal of this study is to demonstrate that transplanted hepatocytes into lymph nodes of mice under fat-induced diet could be an effective treatment of metabolic syndrome. This study will be compared to transplant of brown adipose tissue into lymph nodes. Background and Rational: Obesity is a complex medical condition caused by dysregulation of systemic metabolism, excessive accumulation of body fat, insulin resistance and a variety of additional health issues.  Hepatocytes produce bile acids, which are recognized as key regulators of systemic metabolism, particularly systemic energy expenditure. In this pilot study, we propose experiments to transplant hepatocytes into lymph nodes of mice under fat-induced diet and compare to transplant of brown fat tissue into lymph nodes for an effective treatment of metabolic syndrome. Research Plan Overview and Approach: C57BL/6J mice will be separated in 4 groups (No high fat diet, high fat diet, high fat diet with transplantation of cells in lymph nodes, high fat diet with transplantation of cells in peritoneal fat). For the animal under high fat diet (HFD), the diet will be induced for 6 weeks. Body weight (1x/week), basal non fasting blood glucose, glucose tolerance test, serum triglyceride, low density cholesterol, and serum IGF1, IL-6 and FGF21 data will be collected before the 6 weeks HFD and at week 6 of HFD. Animal will be transplanted with cells (hepatocytes or brown adipose tissue) with continue HFD the next 8 weeks, transferred to C3M core (The Center for Metabolism and Mitochondrial Medicine) for metabolic monitoring (Sable Systems Promethion metabolic cages and GTT) and possible Insulin Sensitivity by Hyperinsulinemic Euglycemic Clamp before necropsy. Source: LyGenesis Term: May 1, 2022 - June 30, 2023 Amount: $257,140]]> 172465 0 0 0 https://mirm-pitt.net/mirmold/grant-of-the-month/grant-of-the-month-june-2022/ Tue, 28 Jun 2022 20:22:41 +0000 https://mirm-pitt.net/?p=172525 PI: Mohammad Eslami and David Vorp Title: Endovascular Orifice Detection (EOrD) Device for In Situ Fenestration of Abdominal Aortic Aneurysm Description: Abdominal aortic aneurysm (AAA) is a localized dilatation of the aorta and if left untreated may go on to rupture which is associated with a 90% mortality rate. This is the 15th leading cause of death in the United States with more than 15,000 deaths reported annually. When an aneurysm reaches the maximum diameter criteria (greater than 5.0 – 5.5 cm), clinicians will intervene with either open surgery or endovascular repair (EVAR). For complex AAA cases, a minimally invasive fenestrated EVAR (FEVAR) is preferred over high-risk open surgery, however, fenestrated stent-grafts extend past the visceral arteries (renal, superior mesenteric artery and celiac artery) and must be revascularized after deployment requiring the stent-graft to be prefabricated. Currently, there is only one FDA-approved fenestrated graft on the market, the Cook Zenith Graft, that requires additional imaging for fabrication with a 6 - 8 week delivery time, costs up to 3 times more than traditional EVAR stent-grafts, and can be technically challenging when passing guidewires through the orifices of the fenestrations. The objective of this project is to develop a medical device for endovascular orifice detection (EOrD) which will both locate visceral arteries and perform in situ fenestration. This device can then be applied in the cases of AAA, ascending aneurysms, and traumatic aortic injury. Preliminary in vitro experiments were performed to determine whether visceral arteries could be detected through chelated sheep blood and stent-graft material using infrared (IR) waves. A scaled-up sensor array was built using phototransistors along with an analog to digital converter to detect the reflected IR waves. Distinct signal responses were collected while sweeping the sensor array over the orifice of the visceral artery, confirming feasibility. After an orifice of the visceral artery is detected, we plan to create a fenestration using a low-powered laser or mechanical puncturing mechanism that simultaneously inserts a guidewire to deploy the bridging stents. Our initial EOrD prototype with the proposed approach will be delivered through a catheter sheath and tested for orifice detection, puncture, and guidewire insertion using realistic in vitro AAA phantoms and cadavers. Continuous feedback from our clinical experts will improve design iterations to develop a final prototype that is able to reliably and reproducibly perform in situ fenestration of stent-grafts to treat aortic aneurysms. With our novel device, we can improve patient healthcare and reduce overall costs associated with AAA repair. Source: National Heart, Lung, and Blood Institute Term: April 20, 2022 – March 31, 2024 Amount: $183,375 (one year)]]> 172525 0 0 0