Rowan University

NSF Awards · FY 2024 · 2024-10

This project aims to serve the national interest by producing instructional activities to optimize physics quantitative literacy (PQL) development that are grounded in validated ways that students develop reasoning. Introductory physics is required for many STEM majors, in large part, because developing a strong foundation in quantitative reasoning is recognized as being important for their subsequent studies and careers. This project will center on two broad instructional aims: improving quantitative literacy for all STEM majors through physics course-taking, and helping reduce barriers that prevent students from economically disadvantaged communities from entering STEM majors. Instructors can help all of their students improve their essential quantitative reasoning by making PQL an explicit learning objective. In order for that to happen widely, instructors need effective materials and methods they can adopt and adapt in a variety of contexts, as well as validated assessments to measure PQL and models for analyzing and interpreting the results. The significance of this project is the development and dissemination of these instructional materials. This project aims to accomplish two goals. The first goal is to create an emergent model of PQL development based on student resources. Using methods related to item response theory and knowledge space theory, this project plans to augment analysis of existing multiple-choice tests by defining a partial-credit scoring model that recognizes the value of students’ responses to test items that are partially correct. By analyzing data from students in introductory, middle-division, and upper-division physics courses, the project aims to produce an emergent longitudinal model of PQL development based on the landscape of student responses to test items across multiple courses. The second project goal is to develop, implement and disseminate instructional materials and methods that will be founded on the emergent model of PQL development. These materials will help students conceptualize the algebra and calculus quantitative reasoning that underpins STEM quantitative literacy and will be disseminated widely across a variety of learning environments to broaden the impact for a diverse group of learners. The model of PQL development produced will be used as a framework to guide the production and refinement of: 1) modular, cooperative activities that can be used in small group settings, think-pair-share lecture settings, or as homework, and 2) formative assessment questions that can be used on tests and quizzes. The NSF IUSE: EDU Program supports research and development projects to improve the effectiveness of STEM education for all students. Through its Engaged Student Learning track, the program supports the creation, exploration, and implementation of promising practices and tools. 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.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract: Targeting PEN-GPR83 as a strategy to reduce opioid abuse liability. Opioid medications, such as morphine and oxycodone, are mainline treatments for pain, however, their use is limited by side effects such as tolerance, dependence, and addiction. Our data demonstrate that GPR83 antagonist Cpd 25, blocks morphine reward while enhancing morphine antinociception suggesting that GRP83-based targeting could be used to reduce the abuse liability of opioids while enhancing their analgesic effects. The first step in validating the potential of GPR83 as a target to reduce abuse liability is to unravel the neurobiological mechanisms by which GPR83 interacts with the antinociceptive pathways. The descending pain modulatory pathway is a critical site for the action of opioids due to the activation of mu-opioid receptors (MOR) on GABAergic inhibitory neurons in the periaqueductal gray (PAG). Our data demonstrate that GPR83, whose endogenous ligand is the neuropeptide PEN, is also expressed in this brain region however, the functional interactions between PEN-GPR83/MOR and sources of PEN in the PAG remain elusive. By using a combination of biochemistry, neuroanatomy, electrophysiology, and imaging, we propose to identify physical and/or functional interactions between PEN-GPR83 and MOR in the PAG. Our preliminary data led us to hypothesize that the neurobiological mechanisms that underlie morphine antinociception in the PAG are determined by an interaction between PEN-activated GPR83 and MOR. To test this hypothesis, we propose three specific aims: 1) to determine physical interactions between PEN-GPR83 and MOR in the PAG, 2) to define the functional interaction between PEN-GPR83 and MOR in the PAG, 3) to determine the impact of endogenous PEN release on MOR function in the PAG. At the completion of this project, we expect to determine if the GPR83 pathway is a valid target for strategies aiming to reduce opioid abuse liability.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Our research program focuses on the development of analytical tools to enhance the characterization of complex biological systems. For rapid, real-time analysis of these systems, sensors based on spectroscopic, electrochemical, and mass spectrometric detection have been widely utilized. However, the capability of these approaches to simultaneously monitor multiple analytes suffers without the use of chemical separations. To achieve sensor-like performance with a separations-based platform, this project focuses on the creation of a liquid chromatography-mass spectrometry (LC-MS) platform for near-universal, real-time online measurement of targeted small molecule metabolites. High-throughput gradient LC separations at capillary-scale flow rates will be achieved through system miniaturization and improved microfluidic mixing combined with a droplet-based injection approach. Improved analyte selectivity and sensitivity for targeted metabolites will be achieved with an online benzoyl chloride derivatization device. To improve the temporal resolution of sampling, the derivatization technique will be adapted to a segmented flow droplet format. Dual column re-equilibration will further increase throughput by 20%, achieving an overall method cycle time of 10-15 s. By combining these fundamental advances in separation science, a transformational measurement platform will be achieved. The system will be used to specifically probe: (1) neurotransmitter release from organoid cell models of traumatic brain injury, (2) polyamine secretion during bacterial biofilm formation, and (3) cell culture media nutrient depletion observed during therapeutic antibody manufacturing.

NIH Research Projects · FY 2024 · 2024-09

Project Summary Children with autism spectrum disorder (ASD) frequently engage in severe destructive behavior that presents significant risks to themselves and others, poses substantial barriers to community integration, and results in high familial and societal financial impact. Despite the efficacy of behavior analytic (BA) interventions for decreasing destructive behavior, to produce meaningful outcomes in the natural environment, treatment effects must transfer to natural change agents, such as parents. Parents are often provided with brief in-person training with therapists modeling and practicing procedures and relapse is common. Although parent training on BA interventions for destructive behavior leads to parent skill acquisition, parents experience in-person training barriers, such as time, financial burden, transportation, and childcare, as well as concerns with the quality of training delivered, such as unrealistic training with therapists and a lack of comfort with therapist practice. To address these barriers, we propose to refine and test a novel virtual reality (VR) parent training tool that allows parents to practice intervention implementation in the comfort of their own home at times convenient for their schedule and quality barriers by closely resembling scenarios parents encounter with their own child. Specific aims of this project are to 1) To pilot a fully customizable, in-home VR training tool for caregivers to learn and practice behavioral strategies for managing their child’s challenging behavior, and 2) To assess the acceptability, feasibility, and preliminary efficacy of a VR training tool using a randomized pilot trial with caregivers and clinicians. In this proof-of-concept study, we will determine skills acquired, treatment fidelity, training adherence, generalization of skills, usability, acceptability, and cost effectiveness of the VR- based training compared to a standard of care control group who receives in-person training with a therapist. The program will be customized to match the specific child, specific target behaviors, context in which the behavior occurs, and specific treatment components. Parents will be exposed to a treatment challenge to prepare for the durability of children’s destructive behavior. The proposed VR tool is individualized, realistic, flexible, safe, and has the potential to transform caregiver training programs for ASD, improve outcomes for children with ASD, and increase caregiver confidence, satisfaction, and well-being.

NSF Awards · FY 2024 · 2024-09

The broader impact of this I-Corps project is the development of microsensors for real-time monitoring of fuel cell membrane degradation in electric vehicles. This diagnostic tool will provide researchers with valuable insights into degradation mechanisms, allowing for targeted improvements in performance and durability. By increasing the efficiency and reliability of hydrogen fuel cells, this technology will contribute to environmental sustainability. The technology also holds the promise of economic benefits by reducing reliance on limited natural resources. By exploring various market segments and conducting extensive and intensive customer discovery, starting with fuel cell electrical vehicle companies, the project will enhance the understanding of existing methods and customer challenges. The potential commercial impact on the transportation industry and companies focused on sustainable clean energy development using hydrogen fuel cell power systems will be thoroughly examined. This comprehensive approach will help identify new opportunities and refine the technology to effectively meet market demands. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of the technology. This solution is based on the development of ion-sensitive microsensors, chosen for their affordability, compactness, durability, and suitability for continuous real-time monitoring of fuel cell membrane degradation. In low-temperature proton exchange membrane fuel cells, radical attacks cause polymer chain breaks and irreversible reactions, leading to thinning of the ionomer and the release of fluorinated and other degradation materials into the reactant outlet streams. These attacks compromise the performance and stability of the membrane electrode assembly. To combat this, the technology employs highly fluoride-sensitive membranes for microsensors, integrating them into a thin insulator layer in the transistor gate. The choice of insulator layer enhances the sensor's selectivity and sensitivity. The design includes an extended gate field-effect transistor, which separates the gate from the transistor, facilitating better integration with the fuel cell exhaust system. Small changes at the gate influence the drain-source current, enabling sensitive, label-free detection at the part-per-billion level. This innovative solution aims to provide effective monitoring of fuel cell membrane degradation, thereby improving the performance and durability of fuel cells. 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.

NSF Awards · FY 2024 · 2024-08

The National Science Foundation (NSF) Graduate Research Fellowship Program (GRFP) is a highly competitive, federal fellowship program. GRFP helps ensure the vitality and diversity of the scientific and engineering workforce of the United States. The program recognizes and supports outstanding graduate students who are pursuing research-based master's and doctoral degrees in science, technology, engineering, and mathematics (STEM) and in STEM education. The GRFP provides three years of financial support for the graduate education of individuals who have demonstrated their potential for significant research achievements in STEM and STEM education. This award supports the NSF Graduate Fellows pursuing graduate education at this GRFP institution. 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.

NIH Research Projects · FY 2024 · 2024-08

Henry, Michael F. Abstract The goal of the proposed research is to define the mechanisms of ribosome assembly within mitochondria. While remarkable progress has recently been made towards understanding the structure of mitoribosomes, the unique pathways and factors that facilitate their biogenesis remains largely unknown. Dysfunctional mitoribosome assembly abolishes the synthesis of several essential components of the respiratory chain, which can compromise cellular energy production and generate reactive oxygen species that promote degenerative disease, aging, and cancer. Thus, a clearer understanding of how these highly complex macromolecular structures are assembled is necessary to better understand mitochondrial disease. To gain insight into this process, this proposal will examine how an evolutionarily conserved yeast protein called Mam33 effectively chaperones a subset of newly imported mitoribosomal proteins and facilitates their incorporation into the assembling large subunit. This mitoribosomal chaperone contrasts with those in bacterial and eukaryotic assembly pathways because it binds multiple mitochondrial ribosomal proteins (MRPs), rather than a single ribosomal protein. This and emerging data suggest that mitochondria might minimize the complexity of ribosome biogenesis by forming small RNA-free preassembly blocs complexed with Mam33, rather than the individual addition of MRPs observed for bacterial and eukaryotic cytosolic ribosomes. The first aim will determine the composition and binding characteristics of Mam33-MRP preassembly complexes. These experiments will determine 1) the number and composition of the preassembly complexes, 2) their binding domains and 3) whether they can form without Mam33. This information will advance our understanding of Mam33 function and mitochondrial ribosome assembly chaperones in general. The second aim will assess the binding properties of Mam33- MRP preassembly complexes. These experiments will 1) establish whether Mam33 targets the N-terminal regions of its mtLSU client proteins, 2) delineate the docking sites for its 5 known mtLSU cargo proteins, 3) identify potential new interactants and 4) examine Mam33-client protein incorporation at a specific mtLSU assembly step. Since Mam33 is conserved in eukaryotic organisms, information gained in yeast will be applicable to human disorders. In human patients, bi-allelic mutations in its ortholog p32/HABP1/gC1qR cause severe multisystemic defects in mitochondrial energy metabolism, which directly result from oxidative phosphorylation deficiencies and mitochondrial instability. Furthermore, p32 overexpression has been detected in nearly all tissue specific forms of cancer and associated with poor prognosis. For these reasons, understanding the physiological role of this protein in the mitochondrion is timely.

NIH Research Projects · FY 2024 · 2024-08

ABSTRACT Multiple myeloma (MM) is a plasma cell malignancy. Treatment usually involves a proteasome inhibitor, dexamethasone, and an immunomodulatory or chemotherapeutic treatment, with or without autologous stem cell transplantation. Because of intrinsic or acquired medication resistance, all myeloma patients eventually relapse. The expression of the prosurvival members of the Bcl-2 family, particularly Mcl-1, is a key process in the survival of myeloma cells. Because Mcl-1 is a critical mediator of disease progression and an important mechanism in the acquisition of resistance to therapy it is reasonable to ask if MM patients, particularly those at relapse, would benefit from an Mcl-1-targeted therapy? A few selective Mcl-1 inhibitors are currently being developed or are being tested in clinical trials, but unfortunately, most of the previous studies were terminated because of undesirable side effects, especially cardiac toxicity. To address this need, we developed a novel Mcl-1 inhibitor, KS18, to investigate the mechanistic underpinning of Mcl-1 role in MM, and to determine feasibility of Mcl-1 inhibition as a therapeutic strategy. Therefore, the rationale for this research is to determine whether our novel Mcl-1 inhibitor can be used along with the existing chemotherapeutic agents to effectively kill resistant myeloma cells, thus, inhibit or prevent MM relapse. Our preliminary studies demonstrated that unlike chemotherapy, KS18 kills resistant cells, suggesting that it could be combined with traditional chemotherapy to treat MM while minimizing the possibility of resistance development more effectively. To evaluate the efficacy and the likely mechanism of action of KS18 in combination with existing MM treatments, we propose the following Specific Aims: First, is inhibiting Mcl-1 via KS18 sufficient to reverse the acquired chemotherapeutic resistance in MM in vitro? We will test KS18 alone and in combination with therapeutic agents used in treatment of MM, including with bortezomib, venetoclax or as a third agent in combination with bortezomib and dexamethasone, which is part of clinical standard of care for MM patients. Second, can Mcl-1 inhibition reverse bortezomib resistance in MM in vivo? We will determine how Mcl-1 inhibition modulates the acquired resistance to chemotherapeutic agents, and third, what is the efficacy of Mcl-1 inhibitor and bortezomib combination in refractory and relapsed patient samples? We will investigate the efficacy of the KS18 and bortezomib combination in patient samples. These significant discoveries would demonstrate the efficacy of targeting anti-apoptotic protein Mcl-1 in MM as well as other cancers for modulating relapse, providing needed preclinical validation necessary for clinical translation. This contribution will be significant because it is expected to have broad translational importance in the treatment of MM. Furthermore, this proposal will enhance the infrastructure of research and education at Cooper Medical School of Rowan University (CMSRU), offering biochemical and biomedical research experiences to underserved minority students, who would otherwise lack such opportunities.

NIH Research Projects · FY 2025 · 2024-08

The Cumberland Bridge to Rowan (CB2R) plan is a distinctive, multilayered research education program in biomedical sciences to increase the pool of students from diverse backgrounds entering biomedical careers that is based on the assessed needs of its partnering institutions. The program is deliberately designed to support the NIH’s goals of increasing the diversity and improving the quality, perspective, and creativity of the biomedical workforce by pairing a well- regarded, highly diverse county college in an impoverished county with a robust and growing research university in a wealthier area seeking to diversify its own student body. CB2R’s goals are to enhance the pool of talented, low-income UR students at RCSJ who successfully transfer to RU and complete their baccalaureate degrees. These goals are supported by the CB2R plan to: ● Promote low-income students’ participation in research through stipend and tuition support. ● Provide academic, advising, and mentoring support to community college and transfer students. ● Support community college students’ development of scientific and quantitative skills. ● Engage students in microbiology and bioinformatic research at the community college and provide diverse research opportunities at the university. ● Provide articulated academic programming and customized transfer activities designed to decrease students’ time to completion; greatly improve their skills preparation; and ensure their academic success and progress toward graduate programs and/or the biomedical research workforce. ● Develop a culture of research at the community college level and strengthen collaborative relationships among community college and university colleagues. Overall, the CB2R partnership between Rowan University and Rowan College South Jersey- Cumberland will strive to increase the retention of underrepresented, low-income RCSJ Biomedical Science students graduating with an associate degree and increase transfer of underrepresented, low-income RCSJ Biomedical Science students to RU as it prepares trainees to enter the biomedical workforce.

NSF Awards · FY 2024 · 2024-08

The well-being of engineering students is critical to understand given the mental health crisis that is accelerating on college campuses across the country. Engineering is known for its culture of hardship which negatively impacts the well-being of its students. Engineering students must navigate that culture of hardship as they examine and determine what types of careers they will pursue in the future. Given these connections, this project explores how engineers think about their well-being and careers in tandem. Identifying connections between the two, and how they change, will help researchers and practitioners support the well-being and career development of engineering students, leading to a thriving STEM discipline on and off college campuses. Engineering students who are better able to thrive are more likely to continue into thoughtful and impactful engineering careers that are apt to positively impact the country's competitiveness. This primarily qualitative longitudinal project uses interviews and concept maps to explore how students perceive connections between their well-being and future goals as engineers, and how these conceptualizations grow and change over time. A thematic approach aids the analysis. The work will also leverage a novel machine learning method, network analysis, to identify quantifiable changes in engineering students' concept maps. Given this project's novel contributions to nascent well-being research in engineering education, the project findings will lay important groundwork for future studies on student well-being. Researchers and practitioners can use the work to improve the concurrent well-being and career development processes that engineers are hypothesized to engage in as they pursue their degrees. This work supports broader salutogenic discussions surrounding human development and thriving which will lead to greater contributions to the economic and social well-being of people in the United States. This project is supported by NSF's EDU Core Research (ECR) program. The ECR program emphasizes fundamental STEM education research that generates foundational knowledge in the field. Investments are made in critical areas that are essential, broad and enduring: STEM learning and STEM learning environments, broadening participation in STEM, and STEM workforce development. 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.

NSF Awards · FY 2024 · 2024-07

Dr. Erik Hoy of Rowan University is supported by an award from the Chemical Theory, Models, and Computational Methods program in the Division of Chemistry to develop comprehensive methodologies that facilitate the design of molecular-scale quantum electric and magnetic field sensors. By measuring minute changes in the quantum states of a system, molecular-scale quantum sensors could provide a level of sensitivity and precision far beyond that of current technologies, with the potential to revolutionize sensing technology in areas ranging from medical imaging to GPS navigation. Obtaining that level of sensitivity and precision, however, requires designing molecular-scale quantum sensors with multiple interacting and long-lived quantum states. To achieve this, Dr. Hoy and his research group will develop comprehensive quantum methodologies for describing multi-state quantum dynamics in single-molecule-scale sensors. These methods will generate the insights needed to create realizable molecular quantum sensor designs that are sensitive enough to detect a single charge interacting with a single sensor. To build the national quantum workforce needed to translate these sensor designs into practical devices, Dr. Hoy will create a multi-level educational program to train undergraduate and community college students to become the next generation of quantum scientists. The key impediment to developing practical molecular quantum sensors with single charge sensitivity is maintaining long-lived coherence in an entangled molecular-scale sensor. Resolving this issue requires a thorough understanding of the dynamics of coherent electronic states. To accurately model coherent electronic states and ensure consistent agreement with experimental results, open quantum transport methodologies with a robust description of multireference electron correlation are required. However, current open quantum transport methods are limited either by their descriptions of electron interactions or the use of a linear response formalism which limits the accuracy of quantum simulations for open systems. To address both limitations, Dr. Hoy and his research group will develop time-dependent nonequilibrium Green’s function (NEGF) implementations for open quantum systems incorporating multiconfigurational molecular electronic structure methods based on pair density functional theories. These multiconfigurational NEGF methods will be used to design molecular-scale quantum sensors with both high sensitivity and long-lived electronic coherence. In addition, to enhance the national quantum workforce, Erik Hoy will develop new low-cost computational clusters and corresponding educational materials for teaching high-performance computing skills in chemistry courses and host interactive computational nanoscience workshops and seminars for undergraduates and community college students in South Jersey. 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.

NIH Research Projects · FY 2026 · 2024-05

ABSTRACT: Multiple myeloma (MM) is a plasma cell cancer that causes an overabundance of malignant, terminally developed B cells in the bone marrow. The outcomes for patients with MM have improved significantly due to advancements in innovative therapies such as proteasome inhibitors, immunomodulatory agents, and immunotherapy. However, relapse remains inevitable for nearly all patients, and long-term survival gains remain limited. One possible explanation for this conundrum is the concept of MM stem-like cells (MMSCs). ALDH is a class of NAD (P)-dependent intracellular enzymes involved in retinoic acid metabolism whose activity is elevated in MMSCs. In MM patients, ALDH overexpression is related with chemo-resistance, clonogenic potential, and a poor prognosis. Furthermore, ALDH shields MMSCs against the toxicity of chemotherapeutic medicines. We anticipate that regulating the ALDH pathway would be a viable technique for combating relapse and refraction in MM. Recently, we created the isatin-based small molecule inhibitor KS100, which targets many ALDH isoforms. The rationale for this project is to evaluate the ALDH isoforms responsible for the clonogenic potential and stem-like properties of MMSCs, determine whether KS100 effectively kills ALDH overexpressing MMSCs, and whether this multi- isoform ALDH inhibitor could be combined with a traditional proteasome inhibitor (bortezomib) to more effectively treat MM. To achieve this purpose, we propose the following Specific Aims. Aim 1, Determine the effect of ALDH inhibition on bortezomib resistance in a MM xenograft model. We intend to look into the influence of nano-KS100 (a liposomal version of KS100) on the growth and stemness of MM tumors. To evaluate the preclinical potential of nano-KS100, we will employ the NOD-SCID-IL2R gamma null (NSG) mouse model. We will investigate if nano-KS100 could be utilized in combination with bortezomib because combination regimens are an important aspect of MM treatment. Aim2, Determine the role of ALDH isoforms in maintaining the resistance and stemness of MMSCs. We will investigate the role of ALDH isoforms (ALDH1A1, ALDH2, and ALDH 3A1) in the aggressive phenotype of MMSCs. We will overexpress specific ALDH isoforms and study their impact on resistance and stemness. Finally, we will determine the extent to which KS100 affects the MMSC phenotype. These noteworthy discoveries would illustrate the usefulness of targeting ALDH enzymes in MM and other malignancies for regulating relapse, providing the requisite preclinical confirmation for clinical translation. This contribution will be significant since it is expected to have broad translational significance in the treatment of MM. Furthermore, this project will enhance the research and educational infrastructure at Cooper Medical School of Rowan University (CMSRU), providing students with valuable opportunities to engage in biochemical and biomedical research that might not otherwise be accessible to them.

NIH Research Projects · FY 2026 · 2024-05

1 Long-bone fractures such as those in the femur afflict more than 430,000 Americans per year and are 2 rising due to the aging population. Such fractures are serious injuries that require surgery. Aligning the long bone 3 fragments requires high precision in the presence of a huge traction force and is performed manually by 4 orthopedic surgeons before fixation. Surgeons have limited visual feedback even with repeated X-ray images, 5 and rotational malalignment of 10° or more after fracture fixation occurs in 28% of patients. Complications include 6 malalignment or nonunion of bone fragments, leg shortening, soft tissue damage, and high exposure to X-ray 7 radiation. 8 This work proposes a surgical robotic system that facilitates long-bone alignment currently performed 9 manually. The long-term objectives are to build and demonstrate a surgical robot that provides a large workspace 10 for the surgeon, can provide traction forces sufficiently large to align the bone fragments without damaging the 11 bones, and provides sub-millimeter precision for alignment. Patient outcomes will be improved by decreasing 12 procedure times and eliminating complications that require repeated operations, such as leg length 13 discrepancies and abnormal gait. The first Specific Aim focus is to develop an image-guided navigation system 14 to automatically align based on surgeon selected positioning on 3D model of the bone fragments. The second 15 Specific Aim focus is to demonstrate use of a force-feedback (haptic) controller for the surgeon to sense the 16 magnitude and direction of the muscle forces and manipulate the robot to align the femur segments. The third 17 Specific Aim is (i) to develop a clinical-grade robotic system that align bone fragments, eliminate the need for 18 manually applied force during alignment, and provide an open surgical field for the surgeon, (ii) to integrate robot 19 with the navigation system and haptic controller, and (iii) evaluate its performance via cadaver testing and user 20 feedback. 21 This design-directed translational research will result in a robotic system that transforms surgical 22 practices for femur fractures and reduces complications. The use of the robot is anticipated to improve alignment 23 by 90% compared to unassisted surgery. The research lays the groundwork for future work to automate bone 24 segment alignment with a new innovative image-guided path-planning algorithm.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY/ABSTRACT Our 24-hour society requires an increasing number of individuals to work rotating shifts to adapt to schedules on a global scale. In the United States, 15 million people participate in some form of shift work. Shift work is associated with the risk of cardiovascular health problems including increased blood pressure (BP), decreased heart rate variability (HRV), ischemic stroke, and cardiovascular disease (CVD). Previous research revealed that shift work induces a misalignment between the endogenous circadian system and the sleep/wake cycle, a phenomenon known as circadian misalignment. Despite the relationship between circadian misalignment and reduced cardiovascular health, there are limited studies on the biological mechanisms responsible for the development of these problems. The nucleus of the solitary tract (nTS) is the first central integration site of peripheral afferents and reflexes. Alterations of the balance within the nTS, of synaptic and/or neuronal excitation, results in elevations in blood pressure. Astrocytes are closely associated with nTS synapses and together with the presynaptic terminal and nTS neuron, form the “tripartite synapse”. In the nTS, astrocytes contribute to synaptic and neuronal activity and their plasticity, as well as pH regulation. The extracellular concentration of glutamate, the primary excitatory neurotransmitter in the nTS, is maintained by astrocytic excitatory amino acid transporters (EAATs). These transporters are critical in maintaining the balance of inhibition and excitation in the nTS via uptake of their respective neurotransmitters. In our preliminary work, we demonstrated that the animal model of circadian misalignment leads to elevated BP and HRV and that these changes were accompanied by decreases in nTS glutamatergic activity. Therefore, in this project, we ask: what is the role of nTS astrocytes in glutamate modulation in the nTS following circadian misalignment and does this pathway contribute to increased BP? Answering this question would address a critical need in our understanding of neural control of blood pressure in response to circadian misalignment. Based on our preliminary data and previous work, we hypothesize that circadian misalignment perturbs the balance of the glutamatergic system in the nTS through disruption of EAATs on astrocytes, leading to an increase in blood pressure. This hypothesis will be tested using an established rodent model of circadian misalignment, which has already been set up in our laboratory. We propose the following aims: Aim 1: Determine astrocytic morphology and expression of EAATs in circadian control of blood pressure. Does circadian misalignment alter this astrocytic morphology and/or EAAT expression? Aim 2. Define the extent to which nTS astrocyte function, specifically EAATs, contribute to nTS circadian regulation of blood pressure and how circadian misalignment alters their activity.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT Opioid analgesics are critical for acute and chronic pain management, but important side effects limit their safety and utility, including tolerance, constipation, respiratory depression, and abuse liability. We have determined that simultaneous activation of µ-opioid receptors (MORs), with the opioid analgesic morphine, and enhancement of GABAergic signaling at α2 and α3 subunit-containing GABAA (α2/α3GABAA) receptors, with the novel imidazodiazepine ligand MP-III-024, produces synergistic antinociceptive and anti-hyperalgesic effects. Preliminary data also indicate that MP-III-024/morphine mixes produce sub-additive effects in behavioral tests sensitive to morphine side effects, supporting further investigation of a dual pharmacological approach that simultaneously targets MOR and α2/α3GABAA to enhance analgesic effects without increasing side effects. We hypothesize that this dual pharmacology approach will result in more effective antinociception with reduced development of critical opioid side effects. To test this hypothesis, we will perform a comprehensive preclinical analysis of the effects of dual MOR-α2/α3GABAA pharmacotherapy in models of pain, tolerance, constipation, respiratory depression, and abuse liability. We will systematically test whether κ-opioid receptors or δ-opioid receptors also contribute to the antinociceptive effects of MP-III-024/morphine mixtures. Finally, we will determine whether bivalent ligands designed to simultaneously target MOR and α2/α3GABAA will produce analgesic effects and represent a new line of medication development. If successful, these studies would identify a new method to enhance opioid analgesia, requiring lower necessary doses of opioid medications, in turn reducing the likelihood of dangerous side effects or the development of opioid dependence and addiction.

NIH Research Projects · FY 2026 · 2022-08

PROJECT SUMMARY Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease (PD), and Huntington’s disease (HD), are rapidly rising in prevalence as our population ages. Despite extensive research, no disease- modifying treatments are currently available to slow or stop progression of these fatal disorders, underscoring an urgent need for new strategies. Protein misfolding and aggregation in the central nervous system are pathognomonic features of all neurodegenerative diseases and have been heavily explored as potential therapeutic targets. A growing body of evidence suggests that pathological protein aggregates exhibit “prion- like” behavior: they template the aggregation of natively-folded versions of the same protein and spread between cells in the brain. Recent findings suggest that phagocytic glia, such as astrocytes and microglia, contribute to prion-like spreading, perhaps due to age-related decline in the degradative capacity of the glial phagolysosomal system. However, the mechanisms that drive prion-like transmission of aggregates between neurons and glia and their potential for therapeutic intervention, remain poorly understood. The overall goal of this R15 renewal application is to elucidate how phagocytic glia recognize and engulf neuronal mutant huntingtin (mHTT) aggregates associated with HD and how this process can both alleviate and exacerbate neurodegeneration. Our prior work identified the scavenger receptor Draper/MEGF10 and the small GTPase Rab10 as modifiers of mHTT aggregate transfer from axons to glia in adult Drosophila brains. Interestingly, Rab10 is phosphorylated by LRRK2, a well-known risk factor for familial PD, on stressed or damaged lysosomes. Thus, the central hypothesis of the proposed work is that the Draper/MEGF10-Rab10 phagocytic pathway mediates spreading of mHTT between cells by promoting escape of prion-like aggregates from the phagolysosomal vesicle network. The central hypothesis will be tested in 3 Specific Aims, which will be carried out in complementary Drosophila and primary astrocyte cell culture experimental models. In Aim 1, we will define Rab10’s roles in Draper/MEGF10-dependent phagocytosis in the presence or absence of mHTT aggregates. In Aim 2, we will determine if LRRK2/Lrrk-mediated phosphorylation of Rab10 regulates mHTT aggregate spreading. In Aim 3, we will identify signals that trigger phagocytic glial recognition of N-terminal fragments or full-length mHTT proteins expressed in neurons. The proposed research is significant in that it will uncover new knowledge about interactions between neurons and phagocytic glia that contribute to neurodegeneration. The proposed research is innovative as it investigates novel mechanistic relationships between Draper/MEGF10, Rab10, LRRK2, and pathogenic protein aggregates. Our findings are therefore likely to inform about common mechanisms underlying HD, PD, and perhaps other neurodegenerative diseases. Further, our complementary in vivo and in vitro experimental models enable a rigorous examination of conserved, disease-relevant pathways in intact brains and isolated primary cells.

NIH Research Projects · FY 2025 · 2022-01

Ultrasound (US) neuromodulation (NM) utilizes mechanical energy from sound to modulate the physiology of excitable cells through mechanosensitive ion channels (MSIC). Its uninvasive bone-penetrating nature combined with a unique focusing capability provides advantages over optogenetics and chemogenetics. Recently, the FDA has approved transcranial USNM. There is a lack of a molecular understanding on how US modulates cellular excitability. Furthermore, not all cells express channels that respond to US. To address these issues, novel experimental systems and techniques will be implemented to extract mechanistic biophysical information and engineer sonogenetic tools for robust transgenic expression. The biophysical effects of US on TRAAK K+ channels were recently characterized because of its potential to serve as a sonogenetic silencer of neurons. The endogenous expression of TRAAK at the nodes of Ranvier also makes it an attractive candidate for inhibitory NM when targeting native myelinated axons in the white matter. During the mentored phase (Aim 1, K99), the fundamental biophysical effects of US will continue to be characterized on TRAAK and other channels. This includes experiments to calculate tension and surveying optimal US parameters to maximize channel stimulation. Preliminary data suggests that the CFTR Cl- channel is sensitive to US. Other MSIC will also be screened to identify those sensitive to US. The next aim (Aim 2, K99/R00) looks to optimize TRAAK and other MSIC into sonogenetic tools. To transform TRAAK into a US-hypersensitive action potential generator, structure guided mutagenesis will be used to increase its sensitivity to ultrasound and permeability to Na+. Aim 3 (R00 phase) looks to implement NM by stimulating endogenous MSIC and transgenically expressed sonogenetic tools. They will be activated in vitro in mouse brain slices and cultured neurons, and in vivo in live mice. In summary, this proposal looks to screen for and optimize the activation of endogenous MSIC with US, and also engineer novel sonogenetic tools. In a short period of time, this work will advance our understanding of the effects of US on MSIC and NM. The long-term goal is to implement these tools for clinical use in minimally invasive NM. This research program will generate a platform of complementary techniques and applicable knowledge that can also be applied by others for further studies in sonogenetics and USNM. Dr. Sorum's mentors, Profs. Brohawn and Adesnik, have expertise that spans many areas of neuroscience including mechanobiology, MSIC structure/function, optogenetics, NM, neural circuits, and behavior. Two additional years of training will allow him to fully develop skills in molecular, cellular and systems neuroscience and merge them with USNM and sonogenetics.

NIH Research Projects · FY 2024 · 2021-09

BRAF, a member of the RAF family protein kinases, works in the MAPK signaling pathway, which controls broad cellular events like proliferation and differentiation. BRAF is the most frequently mutated kinase in human cancers. Furthermore, tumors lacking BRAF mutations are contingent on BRAF activity when there are mutations in upstream pathway members, such as RAS or growth factor receptors. Thus, BRAF represents an important target for cancer therapy. Despite three decades of intense research, only recently has a sufficient understanding of BRAF's mechanism creaked open the door to BRAF therapy. However, the current clinical BRAF inhibitors, vemurafenib and dabrafenib, are limited to the class I mutant BRAFV600E. Vemurafenib and dabrafenib, the two ATP-competitive inhibitors, can paradoxically activate non-BRAFV600E and wild-type BRAF, suggesting that BRAF has functions that are independent of its kinase activity. Therapeutic strategies for tumors with non- BRAFV600E mutations and wild-type BRAF are still lacking. Gaps in our knowledge contributed to the limitations of ATP-competitive BRAF drugs. The proposed work centers around three questions regarding RAF activation and regulation in health and disease states. Q1: how BRAF structural elements and ATP binding mediate the catalytic-independent functions of non-BRAFV600E and wild-type BRAF? Q2: what is the mechanism of action of the first BRAF allosteric inhibitor developed by our group and how can inhibitors targeting the catalytic and non- catalytic functions of BRAF be developed? Q3: What factors contribute to the non-overlapping functions of RAF isoforms, despite their structural similarity? The PI and her team will address these questions through multidisciplinary approaches, including X-ray crystallography, binding kinetics, phosphoproteomics, live cell imaging, chemical biology, and computational methods. Our findings will not only facilitate a better understanding of the complex biochemical mechanisms of the RAF kinase family, also provide a molecular basis for novel therapeutic approaches targeting BRAF-driven tumors.

NIH Research Projects · FY 2025 · 2021-06

Seeds to STEM (S2S) proposes a bilingual program that educates urban children ages 3- 5, their families, and preschool teachers about the importance of childhood nutrition, early STEM and literacy, and kindergarten readiness in order to address national need to introduce all children to STEM at an early age and reduce rates of poverty, hunger, ill health, and low educational achievement among families living in dense cityscapes.”

NIH Research Projects · FY 2025 · 2021-04

As the 4th-fastest-growing research institution in the U.S., with two medical schools and heavy recent investment in biomedical research infrastructure and personnel, Rowan University is an emerging leader in biomedical innovation in the Mid-Atlantic region. Despite this growth, Rowan maintains a strong commitment to student-centered, experiential undergraduate education. This unique combination makes Rowan University an optimal environment for a new diversity-enhancing NIH U-RISE training program. U-RISE@Rowan will provide comprehensive education and training to broadly educate and engage underrepresented (UR) students in biomedical research opportunities (Aim 1), to build a community of research-driven UR students with the skills for success in biomedical careers (Aim 2), and to generate a pipeline of highly-qualified UR graduates that succeed in doctoral-level biomedical careers (Aim 3). The training program will include four stages: RISE & See; RISE & Strive; RISE & Shine; and RISE & Soar. RISE & See will broadly educate and engage first-year UR students in biomedical research. Highly-motivated candidates will apply for one of five U-RISE@Rowan Fellowships. RISE & Strive will build sophomores’ scientific literacy and practical skills through research experience, foundational coursework, and extracurricular training. RISE & Shine will provide junior trainees with research-focused coursework, intensive research training, and workshops to build their professional skills. RISE & Soar will combine external summer research at a partner R1 institution, a capstone thesis, guided application to Ph.D. programs, and training in scientific citizenship that includes downward outreach by senior trainees to enhance recruitment of UR students interested in STEM careers. All stages of the program include co-curricular training that will be accessible to all UR STEM students interested in biomedical research, with the goal of broadly enhancing UR engagement in undergraduate research and pursuit of biomedical research careers. U-RISE@Rowan will leverage the diversity and unique undergraduate-driven, research-focused environment of Rowan to create a sustainable, scalable program that will yield long-term, far-reaching impact on the diversity of the biomedical doctorate research community.

NIH Research Projects · FY 2024 · 2020-09

ABSTRACT Until recently, N-lysine acetylation was thought to be rare in bacteria, but is now appreciated to affect hundreds of bacterial proteins with diverse cellular functions. Acetylation was initially discovered as a post-translational modification (PTM) on the unstructured, highly basic N-terminal tails of eukaryotic histones. Histone acetylation constitutes part of the “histone code,” and regulates chromosome compaction and various DNA processes, such as gene expression, replication, repair and recombination. In eukaryotes, acetylation regulates many other proteins in addition to histones, involved in a wide array of important biological processes. This observation is also true in bacteria, as evidenced by the characterization of the acetylomes of more than 30 different bacterial species. However, the physiological significance of the vast majority of these modifications remains unknown. In addition, the mechanisms of acetylation and deacetylation, and the bacterial enzymes involved are not completely understood. To address these gaps in knowledge, we have focused on studying the acetylation of the essential, histone-like protein HBsu in Bacillus subtilis. In bacteria, the nucleoid is compacted and organized by the action of nucleoid-associated proteins (NAPs). HBsu is a member of the most widely conserved NAP family, and is considered a functional equivalent of eukaryotic histones. We found that HBsu contains seven novel acetylation sites, and this raised the exciting possibility that these modifications represent a “histone-like” code in bacteria. So far, we discovered that acetylation of HBsu at key lysine residues is required to maintain normal chromosome compaction. Additionally, we identified the second protein acetyltransferase in B. subtilis. The overall goal of our research program is to decipher this code. Our recent progress supports the hypotheses that acetylation of HBsu regulates cell division and sporulation, and that there are additional enzymes involved in regulating acetylation. The short- term goals of this work are to define the enzymatic mechanism of regulation of HBsu acetylation and determine the significance of HBsu acetylation in the regulation of DNA transactions, stationary phase development and drug tolerance. Additionally, we will develop new biochemical and mass-spectrometry based proteomics techniques for the study of acetylation in bacteria. Our long-term goals are to characterize additional HBsu PTMs, identify and characterize novel enzymes of acetylation, and perform a detailed structural and biochemical analysis with acetylated HBsu and novel enzymes. Ultimately, we will design novel inhibitors of bacterial acetylation enzymes or acetylated HBsu and assess their efficacy as potential novel antimicrobial therapies. Together, these studies may demonstrate the existence of a histone- like code in bacteria, an unexpected and exciting new field of biology. Furthermore, these studies will provide the foundation for designing novel antimicrobial drugs that target protein acetylation, either the enzymes or key acetylated targets.