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FEATURED RESEARCH
Development, Piloting and Dissemination of an Integrated Clinical and Social Multi-level Decision Support Platform to Address Social Determinants of Health Among Minority Populations in Baltimore City
PROJECT SUMMARY Achieving a comprehensive assessment of a person's health and addressing health disparities goes beyond just documenting clinical diseases and medical interventions. We must also capture, standardize, analyze, and report reliable information on Social Determinants of Health (SDOH) within operational Clinical Decision Support (CDS) systems that are built-into electronic health records (EHRs). Moreover, to truly have an impact on decreasing health disparities, data analysis is not enough. At the point of care, we must digitally support interactions between medical and social services. Our proposed project addresses many of the hurdles in this process through the application of informatics, social science, health services research, implementation science, and stakeholder engaged research. This project will be undertaken by an experienced interdisciplinary team of investigators with many pre-existing resources. To maximize impact, the academic team will be complemented by an exceptional network of collaborating community, operational information technology, and stakeholder agencies from both the region and nationally. Our goal is to facilitate the integration of available digital information regarding SDOH needs and services into provider EHRs with the intent of improving care for minority and disadvantaged populations with chronic diseases. The first aim will be to integrate both clinical and non-clinical large-scale databases (e.g., EHRs, social risk assessments, and neighborhood characteristics) in order to develop a multi-level CDS tool inclusive of a comprehensive social risk score. As part of this CDS, in collaboration with the Maryland Health Information Exchange, we will also develop an interoperable closed loop referral system between primary care practices and 3 community based (social service) organizations (CBOs). These and all other development phases will build on extensive preliminary work the study collaborators have completed in related domains. The second aim will be to integrate the CDS tool into the established care management support system and workflow and to pilot this Health IT-based intervention using a randomized clinical trial (RCT) design at four primary care practices within the Johns Hopkins Health System (JHHS). The main intent of this CDS-based intervention will be to identify and assess SDOH of African-American adult patients (18+) with low incomes and a high burden of chronic illness, and as needed to refer them to the CBOs participating in this pilot. The third aim will be to assess the acceptability of the CDS tool (including its risk score and referral module) and to initiate dissemination of the data platform in support of its implementation across the JHHS institution, the Maryland statewide (CPC+) primary care program, and potentially nationally. To accomplish this aim, we will collaborate closely with clinical providers, CBOs, and an advisory board made up of the local and national leaders, as well as patients and frontline workers (e.g., community health workers, care managers, and social workers). With the help of several national leaders on our advisory board, we expect to substantially contribute to the broader national agenda regarding the digital integration of SDOH and clinical data into EHR-supported workflows.
Use of Novel Neuroimaging, Neuropsychological Methods, and Retrograde Memory Test to Detect Cognitive and Cerebral Disruption in Veterans with Mild Traumatic Brain Injury
Identification of neuroimaging-based markers sensitive to mild neurotrauma and neuropsychological markers of cognitive disruption is vital toward addressing the complex treatment needs of the large number of Veterans with histories of mild traumatic brain injury (mTBI). Although neuroimaging methods, particularly in the area of diffusion imaging (dMRI) continue to show promise, there are significant limitations in the traditional, diffusion tensor imaging (DTI) based approach in white matter (WM). Specifically, a high degree of heterogeneity of WM axon orientations and sampling from disparate tissue types within a voxel contribute to inaccurate estimates of tissue properties. These limitations, inherent in standard and widely used DTI methods, likely attenuate DTI sensitivity in the detection of mild forms of neurotrauma, particularly in key, complex WM regions shown to be most susceptible to mTBI. Likewise, cognitive research findings in mTBI have been mixed, with conflicting reports and unclear cognitive outcomes that likely cloud and confuse clinical decision-making. The heterogeneity of TBI, differences in injury characteristics, and a non-uniform cognitive profile among affected Veterans likely contribute to the decreased sensitivity and inconsistency shown across studies that have leveraged traditional means- based comparisons of traditional neuropsychological test scores. Indeed, indicators of mTBI often fail to align with imaging findings, cognitive reports, and functional outcomes reported by Veterans with histories of mTBI. In the proposed study, we will apply new tools and methods in order to more sensitively examine WM disruption and neuropsychological performance in 60 Veterans with mTBI and 60 Veterans without a history of TBI. Participants will complete a broad neurocognitive assessment, including a novel test of retrograde memory for news facts, and will undergo a dMRI scan. We propose that leveraging a novel neuroimaging approach—one that is robust to the limitations inherent in standard DTI protocols—will enable investigation of WM proximal to the sulcal depths where all-cause mTBI is thought to inflict the greatest damage given shearing effects at the gray matter-white matter border. We will use dMRI acquisition and analysis methods which combine single and double pulsed field gradient dMRI acquisitions via a novel technique called Joint Estimation Diffusion Imaging (JEDI) to integrate diffusion information at the voxel and subvoxel level. Equilibrium probability (EP), an anisotropy measure that is more robust to the complexities of crossing fibers and partial voluming effects, will be calculated using JEDI. In particular, we will interrogate EP of voxels residing in the sulci at the gray matter-white matter border in the frontal lobe. Simulation and histopathological studies show these regions to be most susceptible to acute and distal effects of mild neurotrauma given the shearing effects that are particularly damaging because of differing tissue densities of the gray-white border. Second, given our recent work showing the sensitivity of newer cognitive methods to detect neuropsychological deficits in mTBI and others with mild cognitive difficulties, we will investigate intra-individuation cognitive performance variability (IIV) as a marker of cognitive disruption in order to enhance brain-behavior associations in Veterans compared to traditional comparison of group means. We will also administer a new cognitive tool, the retrograde memory news events test (RM-NET) to determine if it is sensitive to the cognitive deficits and TBI characteristics in Veterans with chronic mTBI. Taken together, the proposed study presents an opportunity to investigate WM disruption within brain regions vulnerable to mTBI using a novel neuroimaging approach (JEDI), further assess a promising cognitive concept (IIV) and new cognitive test (RM-NET), which may improve the evaluation of clinical outcomes following mTBI, and examine potential associations between IIV and WM disruption in Veterans with mTBI. Such cutting-edge work can lay the foundation for enhanced understanding of the neurobiological underpinnings of mTBI and persisting postconcussive symptoms in Veterans with neurotrauma and may identify neuroimaging biomarkers and cognitive abilities useful to evaluate treatment response in future clinical trials.
Mechanisms of Wg/Wnt regulation by glypican Dlp
PROJECT SUMMARY Wnt signaling is an evolutionarily conserved pathway that regulates several cellular behaviors such as cell proliferation, survival, differentiation, and migration to promote tissue homeostasis. Of note, the Wg/Wnt signaling pathway is important for tissue patterning and is often deregulated in epithelial cancers. Secreted Wnt ligands are distributed in the extracellular space to promote paracrine and long-range signaling in target cells. These paracrine and long-range functions of Wnts are dependent on extracellular Wnt availability, which in part is dictated by cell-surface glypican, Dally-like protein (Dlp). In this proposal, I will focus on molecular mechanisms that dictate Dlp-mediated regulation of Wnt availability and signaling. Dlp’s role in regulating Wnt signaling has been described as ‘biphasic’: By continual binding and release, Dlp simultaneously promotes long-range signaling and restricts paracrine signaling, ensuring proper ligand availability at both ranges. The Page-McCaw lab established Drosophila germarium, a tissue where oogenesis occurs, as a model to study mechanisms that define Wnt signaling ranges, and identified a novel Dlp/Mmp2 (Matrix Metalloprotease 2) module that modulates paracrine and long-range Wnt signaling in the germarium. Specifically, I found that proteolytic cleavage of Dlp by Mmp2 alters its subcellular localization and function to modulate Wnt availability. Additionally, my preliminary data suggest that Dlp/Mmp2 may regulate Wnt signaling in epithelial tumors to promote tumor growth. In Aim 1, I will investigate the molecular events that occur downstream of proteolytic cleavage of Dlp to modulate Wg/Wnt availability and signaling in the germarium and tumors. The extracellular Wnt distribution is tightly linked with its production and secretion. I found that Dlp can modulate Wg (Wnt-1) production in source cells in the germarium. Wg production in source cells in germaria is tightly regulated and this regulation is crucial for proper oogenesis. Additionally, I found that Dlp interacts with non-ligand proteins (a finding that has not been previously reported) that communicate with intracellular cytoskeletal machinery, potentially to modulate cell adhesion and/or shape. In Aim 2, I will investigate novel mechanisms of how Dlp regulates Wnt ligand production and long-range Wg distribution to facilitate long-range Wg signaling. These investigations will uncover previously unappreciated roles of cell-surface glypicans in regulating Wnt signaling and elucidate novel paradigms of developmental strategies employed in multicellular organisms to maintain tissue homeostasis.
Neuregulin-1 as a Therapeutic Treatment of Ischemic Stroke
PROJECT 1 ABSTRACT Ischemic stroke is the leading cause of serious long-term disability and the 5th leading cause of death in the United States. Significant racial/ethnic health disparities in stroke outcomes exist, particularly for African- Americans. Revascularization of the occluded cerebral artery, either by thrombolysis or thrombectomy, is the only effective therapy. However, only about 5-7% of acute stroke patients in the United States receive revascularization, so there is a significant need to develop new therapeutic strategies for stroke. We demonstrated that neuregulin-1 (NRG-1) reduced ischemia-induced neuronal death and neuroinflammation in rodent stroke models with a therapeutic window of >13 hours. NRG-1 administration also resulted in a significant improvement of neurological function when administered 3 days following ischemia, suggesting a role in neuronal repair. In addition, NRG-1 prevented neuronal injury and improved blood brain barrier integrity in animal models of brain hemorrhage. NRG-1 showed significant efficacy for improving cardiac function in multisite phase II patient studies and is currently in phase III human clinical trials for heart failure. NRG-1 has also shown a survival benefit in subjects with severe heart failure, which the ongoing phase III study in China is designed to assess for approval. The Good Manufacturing Practice (GMP) manufacturing of NRG-1 has also been approved for use in Phase III clinical trials in the US by the Food and Drug Administration (FDA). These studies provide evidence that NRG-1 represents a novel, safe, neuroprotective strategy that has potential therapeutic value in treating individuals after acute ischemic stroke. The overall goal of this project is to develop NRG-1 as a novel neuroprotective stroke therapy. To achieve our goal, we propose the following set of specific aims: (1) determine the neuroprotective efficacy and therapeutic window for of NRG-1 following ischemic stroke; (2) evaluate therapeutic effect at time points relevant to stroke thrombectomy patients; (3) examine whether NRG-1 can reduce toxicity and extend the therapeutic window for tissue plasminogen activator (t-PA) following ischemic stroke; and (4) investigate the spatiotemporal regulation of transcriptional profiles initiated by NRG-1 induced neuroprotection following ischemic stroke. These findings could support the development of clinical studies using NRG-1 alone or in conjunction with other therapies, such as thrombolysis and thrombectomy, for the treatment of patients with acute stroke. If successful, this study could aid in the progression of NRG-1 towards clinical trial, FDA approval and deployment as a new treatment for ischemic stroke.
A tango between magnons and phonons in 2D van der Waals insulating magnets
Non-technical: Magnons and phonons, which are quanta of spin waves and lattice vibrations respectively, represent two fundamental collective excitations in condensed matter. In general, magnons and phonons are studied separately. Nevertheless, in magnetic solids with strong spin-lattice interactions, magnon-phonon coupling plays a key role in determining magnetic and thermal properties. Thus far, experimental studies of magnon-phonon coupling in van der Waals magnets, which emerge as a fertile playground for the discovery of novel physical phenomena, remain a largely unexplored research frontier. This project studies the magnon-phonon coupling in van der Waals insulating magnets by utilizing neutron scattering and thermal transport techniques. This project offers an excellent educational experience for young researchers to utilize cutting-edge facilities for scientific research on quantum materials. In addition to training graduate and undergraduate students, this project also supports scientific research activities by engaging K-12 students, attracting underrepresented students to research, and developing workshops. Importantly, this project serves as a platform to train the next-generation of neutron scattering scientists and therefore grows the user community of cutting-edge facilities in national laboratories. Technical: This project studies magnon-phonon coupling in van der Waals insulating magnets to understand the roles of magnons, phonons, and magnon-phonon coupling on thermal transport and thermodynamics of these systems. Specifically, the work addresses the following key scientific questions with neutron scattering and thermal transport techniques: (i) how does the magnon-phonon coupling depend on the symmetry of magnetic ground states? (ii) how does the spin-lattice interaction depend on the electron occupancy on d orbitals of magnetic transition-metal ions, and what is the impact of this on the magnon-phonon coupling? (iii) How does the magnon-phonon coupling vary with the spin-orbit interaction? (iv) How does the magnon-phonon coupling affect materials’ thermal transport and thermodynamics properties? The answers to these questions provide unprecedented knowledge about the coupling between magnons and phonons as well as their impact on thermal properties of van der Waals materials, which are essential for applications of these materials in spin caloritronics and magnon spintronics. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
