Northeastern University

NIH Research Projects · FY 2025 · 2015-07

This proposal is a renewal for the tremendously successful two-day symposium “Chemistry and Pharmacology of Drugs of Abuse” (CPDA) symposium that first took place in 2016 under the auspices of the Center for Drug Discovery (CDD), Northeastern University, Boston, Massachusetts. The primary aim of the symposium is to serve as an interdisciplinary exposition of the most recent, important, research-related advances in (pre)clinical research related to Substance Use Disorder (SUD). Substance Use Disorders (SUDs) and addiction are pervasive threats to global public health, and the nature of the threat is ever-evolving and changing. Our goal is to address gaps in current knowledge concerning SUD disease mechanisms and treatments at the root of our limitations in solving these medical challenges. A major theme is the integration of medicinal chemistry, structural biology, pharmacology, behavioral pharmacology and clinical practice to inform the design, synthesis, optimization, and (pre)clinical profiling of new agents for their therapeutic potential. SUD biology and etiology are complex. Behavioral, environmental, and (epi)genetic factors conspire to modulate neuronal circuits to affect vulnerability, cognition, social behavior, and emotional state in ways that help establish a SUD phenotype. The details of these neurobiological processes are not well understood. In addition, better-standardized animal paradigms of drug-seeking and --taking are required to better model clinical SUD pathology and be used to assess the potential of novel SUD drugs more accurately. Despite significant advances, there is a frustratingly limited number of safe and effective pharmacotherapies available to attain durable abstinence. Our continuing aim is to focus the meeting entirely on Substance Use Disorder and bring together leading practitioners from each field. Moreover, there are emergent threats to at-risk SUD populations, such as “designer drugs” that lack effective pharmacotherapy and require ongoing vigilance and effort to combat. We aim to include topics that address emergent issues in each year’s program as identified by NIDA community leaders and leading research. Such a gathering offers a rich opportunity to expose young scientists to the field. We aim to inspire and encourage the next generation of researchers to devote themselves to this endeavor. We have made considerable efforts to welcome scientists from all populations and we aim to expand these efforts. A focused meeting on SUD responsive to emergent threats is of high value. It has garnered much support from the SUD research community and various constituencies, from basic researchers to healthcare providers and public health officials. This included scientists from biotechnology (e.g. Astraea Therapeutics), leading biomedical research centers (e.g. Scripps Research Institute), research-intensive clinical centers (e.g., McLean Hospital/Harvard Medical School, Icahn School of Medicine at Mount Sinai) and representatives from the City of Boston Mayor’s office. Our goal is to further raise the public profile of our symposium

NIH Research Projects · FY 2025 · 2015-07

The goal of this first T32, 5-year renewal of the successful “Transdisciplinary Training at the Intersection of Environmental Health and Social Science” is to prepare 10 doctoral students and 8 postdocs (4 environmental health and 4 social science) to be future leaders in social science environmental health science collaborations. This overall goal has the following objectives: 1) Educate trainees in a new research trajectory that combines environmental health and social science; 2) Teach trainees about community-based participatory research (CBPR), informal science education, and public participation in research; 3) Train researchers to integrate CBPR practices into existing and emerging research programs; 4) Provide hands-on training at a science-based community-based organization (CBO) to demonstrate to trainees how it does research and interfaces with advocacy on emerging contaminants and technologies. This training program is unique in that is co-directed by an academic institution – Northeastern University's Social Science Environmental Health Research Institute and a non-academic institution - Silent Spring Institute, a science-based environmental non-profit organization. It builds upon 15 years of collaborative research and training activities between the two partners. Trainees are equipped to improve environmental health through: core and elective coursework, two dedicated seminar series for trainees, engagement with CBOs that use novel tools for robust exposure and dose estimates, participatory research methods such as community-based participatory research and civic science, and reflexive research ethics. Trainees will be part of research teams at both institutions, including processes and ethics of reporting back biomonitoring and personal exposure results to participants; data sharing and privacy protection; exposure, remediation, health effects, and regulatory and policy issues of per- and polyfluoroalkyl substances, modeling of emerging contaminants in Cape Cod drinking water, water access and equity; development of exposure biomarkers for breast cancer studies; and development and application of low-cost community sensors. Trainees will also learn how to work with the news media. Pre-doctoral trainees will be funded for 3 years each, and the postdoctoral trainees will be funded for 2 years each.

NIH Research Projects · FY 2026 · 2015-04

The objective of “Research Opportunities for Undergraduates: Training in Environmental Health Sciences (ROUTES)” renewal is to build on a decade of success in preparing undergraduate students to pursue careers as scientists, engineers, and researchers in environmental health (EH) fields. The program leverages Northeastern University's (NU) unique cooperative education structure to provide intensive research training that integrates theoretical knowledge with hands-on laboratory experience. Specific Aims: (1) Identify and recruit qualified students to EH research opportunities at NU and beyond through a merit-based selection process; (2) Engage and train Northeastern undergraduate students in EH research through cooperative education experiences on-campus in faculty research labs and in external partner research settings; and (3) Promote mentoring and build community among ROUTES student participants and faculty mentors through a robust program of research-related training activities. Approach: ROUTES provides basic and translational research experiences in environmental health science and related disciplines that leverage Northeastern’s (NU) well-known cooperative education (co-op) structure. Our program’s participating faculty and external partners provide mentoring and research experiences in health sciences, engineering, and environmental sciences through: (1) full-time, paid co-op research experiences for six months for students selected based on merit (ROUTES Scholars), (2) targeted mentoring and support services to assist Scholars in pursing graduate studies and research careers, and (3) cohort building and professional development. We have increased the number and types of supported experiences through the addition of off-campus research partners in addition to on-campus faculty, and leveraging mentor-provided funds for student salary. We will develop an accompanying credit-bearing course on research methods and career preparation specifically designed for our ROUTES Scholars. The program evaluation plan includes well-designed assessment and continuous improvement to maximize efficacy. Expected Results: ROUTES will enlarge the pool of undergraduate students interested in exploring environmental health research careers and create opportunities for up to 60 students over five years to participate in paid hands-on research experiences, mentoring, and complementary activities. Through these methods, ROUTES will continue its long history of encouraging students to pursue research careers in these fields, thus addressing a critical national need.

NIH Research Projects · FY 2025 · 2014-12

SUMMARY/ABSTRACT Human African trypanosomiasis (HAT) and Chagas disease (CD) are neglected tropical diseases (NTDs). Current drugs show increasing numbers of treatment failure, low efficacy, difficult treatment regimens or severe side effects. In a unique industrial-academic collaboration, the PIs, in collaboration with GSK, ran a high-throughput screen (HTS) of ~46,000 kinase-targeted inhibitors against Trypanosoma brucei, the causative agent of HAT. This resulted in the discovery of 797 potent (T brucei EC50<1 μM; pEC50 6) and selective hits (>100-fold over HepG2 cells) that were sorted into 59 structural clusters, plus 53 singletons. 14 chemotypes including 13 clusters and 1 singleton have been explored for their structure-activity and structure-property relationships. A “parasite-hopping” approach has identified six of these with interesting activity against T cruzi (CD). This competitive renewal outlines a hit-to-lead medicinal chemistry program that will continue to optimize high-priority hit clusters from the original HTS. These have been identified through re-analysis of the original HTS data to place an emphasis on compounds that are cidal and predicted to cross the blood-brain barrier (BBB) which is essential to treat stage 2 of HAT. Additionally, we will employ computer-aided drug discovery to further explore those chemotypes for which we have identified a putative target. We will also perform hit-to-lead medicinal chemistry optimization on the six chemotypes that have been identified as of interest for T cruzi. We will also look for synergistic effects between clusters that have complementary activity profiles (e.g. slow acting, cidal in nature, and fast acting, static in nature) and in combination with standard trypanocidal drugs. Optimization will result in the delivery of high-quality lead compounds from each of these chemical classes, and the lead compounds will meet stringent profiles of cellular potency and selectivity, BBB permeability, physicochemical and metabolic properties, and pharmacokinetic properties in mice depending on the disease targeted. Furthermore, these lead series will display in vivo efficacy in the murine models of disease. The optimization program will be performed under the continuing collaboration between NEU and CSIC, with critical contributions of expertise in drug metabolism and physicochemical properties experiments from AstraZeneca and UCSD. We have developed and implemented a testing funnel that ensures that the optimization process will address the most critical lead criteria. Finally, we will perform the target identification and mode of action studies by different approaches including chemical proteomics, induction of resistance and whole genome sequencing and metabolic fingerprinting. This project will deliver (a) multiple lead compounds for HAT and CD that meet well-defined Lead Criteria; (b) broader profiling of lead compounds against more stringent Candidate Criteria; (c) identification of target for lead series or compound. In this way, we intend to help fill the pre-clinical candidate pipeline for HAT and CD.

NIH Research Projects · FY 2025 · 2014-07

CaNCURE: Cancer Nanomedicine Co-ops for Undergraduate Research Experiences was created by Northeastern University (NEU) and Dana-Farber/Harvard Cancer Center (DF/HCC) to provide immersive research training and education at the interface of nanotechnology, cancer biology, and medicine to attract, retain, and encourage young scientists and engineers to pursue careers in cancer research. The central hypothesis of CaNCURE is that a 6-month, full-time, mentored research experience, accompanied by a rich educational environment providing intellectual immersion in cancer nanomedicine, will lead to persistence in college and motivation for a career in cancer research. With the support of two consecutive NCI R25 awards (2014-24), the CaNCURE program has provided 6-month mentored research experiences for 133 students from 14 different STEM disciplines. Trainees conducted high-impact research in 43 NCI-funded laboratories, published 67 peer- reviewed manuscripts in high-impact cancer and nanomedicine journals, and won 68 research awards. 67% of trainees continued to volunteer in their CaNCURE lab after co-op completion and 36% went on to complete one or more additional cancer research experiences before graduation. Of the 109 students who graduated, 38% went to medical school, 16% went to graduate school, and 40% pursued research careers in the healthcare field. 23 more undergraduates will complete this program by June 2024. Here we seek to renew and expand the CaNCURE program to train 85 new undergraduates during 2024-2029. Traineeships will be provided to 17 students per year spread across 2 co-op cycles (January-June and July-December). To further strengthen the existing program, we propose the addition of 11 new faculty mentors aligned with the NCI’s 2024 strategic goals, formal mentor training, hands-on research training workshops, small-group patient case study discussions, and a CaNCURE advising system to support trainee research efforts after the co-op. The program will achieve its goals through the following specific aims: Specific Aim 1: Provide a hands-on, full-time research experience with a focus in cancer nanomedicine mentored by world-class cancer researchers at NEU and DF/HCC. Specific Aim 2: Provide year-round activities for training enrichment, including weekly seminars, patient case studies, hands-on research training, a reflective e-portfolio, and conference travel. Specific Aim 3: Provide professional preparation for a career in cancer research, including professional skills training, opportunities to network and present research, and resources to enhance career preparation both during and after co-op.

NIH Research Projects · FY 2025 · 2014-02

Abstract The control of movement, in spite of its seemingly effortless execution, belies a complex, multi-level collective of neuromuscular interactions tuned and coordinated through sensory experience. Efficient and flexible behavior in everyday contexts requires neural mechanisms that support rapid updating whenever objects around us, or even our own movements, are disrupted during ongoing motion. As a movement unfolds, the need for predictive or responsive control to correct for contextual perturbations changes. For example, the early stages of an action typically exhibit fast responses to perturbations, suggesting the existence of feed-forward processes that use internal models to predict the sensory consequences. On the other hand, later phases appear to employ continuous sensory feedback to adjust movements. While much is known about updating for postural and arm movements, very little is understood about the neural mechanisms of updating of dexterous movements of the hand as we interact with objects. While the reach-to-grasp cortical anatomy is well described, the causal functional roles of the regions still remain elusive. In particular, it is now becoming clear that the dominant framework which describes reach-to-grasp control as being under the control of independent frontoparietal channels is untenable because it does not explain recent empirical neurophysiological findings. Therefore, the current project aims to leverage non-invasive stimulation to induce transient cortical perturbations, paired with visual perturbations to the task goal and mechanical perturbations of the internal state of the limb, to causally evaluate the contributions of four critical brain regions in components of the reach-to-grasp action. The information derived from this work will provide a more solid background for our understanding of the functional organization of the frontoparietal reach-to-grasp network and, by extension, of hand-arm control coordination. This project will advance our empirical understanding of how dexterous updating of the upper limb, in particular reach-to-grasp actions, are orchestrated by the brain. The knowledge will be immediately applicable and translatable for rehabilitation of upper limb recovery in stroke and other similar disorders, by using error augmentation through visual and haptic platforms to facilitate skill reacquisition and identifying cortical targets for non-invasive neuromodulatory stimulation. These findings will be relevant to the mission of the NIH, with broad interest to clinicians and basic scientists, and will have direct

NIH Research Projects · FY 2026 · 2005-08

Project Summary/Abstract It is well known that stem cell differentiation and cell fate are regulated by mechanical forces and mechanics. We have reported earlier that cell mechanical properties dictate stress-induced spreading and differentiation in embryonic stem cells (ESCs). Other reports have also demonstrated the effect of forces on pluripotent stem cells. However, how force regulates (pluripotent) stem cell differentiation and cell fate at the level of chromatin remains elusive. This is an important question since the chromatin is the hub of gene transcription and DNA replication and DNA damage repair, critical for pluripotent stem cell self-renewal and differentiation and cancer stem cell self-renewal. Our preliminary results chromatin domain stretching but not compression rapidly and nuclear protein LAP2β mediates force transmission from nuclear lamina to chromatin. In addition, RNA polymerase II (Pol II) is recruited and elongated in response to stretching but not compression and demethylation of H3K9me3 is necessary for force-induced gene upregulation. Built on these results, we propose 3 specific aims to elucidate nuclear mechanobiology mechanisms in the living cells. Aim 1: To determine if chromatin stretching is necessary for force-induced stem cell differentiation; Aim 2: To test the hypothesis that H3K9me3 and H3K9ac regulate force-induced pluripotent stem cell gene transcription; Aim 3: To determine if large-strain induced telomere attrition contributes to transition from normal stem cells to cancer stem cells. Our experimental designs are rigorous and the likelihood of generating insightful discovery is high. The long-term goal is to develop novel approaches and strategies to intervene pathological processes like malignant tumors.

NIH Research Projects · FY 2025 · 1998-04

PROJECT SUMMARY Kir3 or GIRK (G protein gated inwardly rectifying K+) channel isoforms are expressed in multiple parts of the body, including the atria of the heart (GIRK1, 4) and platelets (GIRK1, 2, 4). In the heart, activation by the vagus nerve slows down heart rate. GIRKs are critical determinants of heart rate variability (HRV), an index of cardiac health, endowing the heart with the adaptability it needs to make rapid adjustments in heart rate. GIRK channels are attractive drug targets against atrial fibrillation (Afib), the most common arrhythmia. In the last cycle of this grant, we showed that increased Afib prevalence with age results from constitutive activation of PKC by the oxidative conditions of aging, which phosphorylates GIRK4 channels to increase their activity, leading to an increased risk of mortality, stroke and myocardial infarction. Additionally, the lack of specificity of the current antiarrhythmics used poses significant risk for ventricular side effects. This makes rather attractive targets expressed predominantly in the atria, like GIRK channels. Yet the lack of specific and partial inhibitors of GIRK activity in the atria that could reverse Afib, but not inhibit HRV, have been challenging to make. During vascular injury, P2Y12 receptor stimulation activates GIRKs to somehow result in generation of the lipid thromboxane A2 that amplifies platelet activation and recruitment of additional platelets to the site of injury to form clots and stop or prevent bleeding. Even though P2Y12R is the target of efficacious anti-thrombotic drugs, the lack of understanding of GIRK biology in platelet activation and the lack of specific GIRK inhibitors has stalled targeting them for anti-thrombotic effects. In Aim 1 of this proposal, we utilize state-of-the-art computational approaches to design drugs that target specific GIRK isoforms at either of two sites, transmembrane (TM) and cytoplasmic (CP) ones and couple preferentially to either of the two channel gates, the membrane (M) and the cytosolic (C). In Aim 2a, we use these powerful probes to find the balance between reversing Afib and maintaining HRV, thus aiming to address the unmet medical need for GIRK-isoform specific partial inhibitors. In Aim 2b, we also use them to decipher the involvement of GIRKs in platelet-mediated thrombosis. The complementary expertise of the three labs make this a unique team. The Logothetis lab has made seminal discoveries over the years on GIRK structure and function and more recently, drug discovery, while the Noujaim lab has great expertise in Afib and HRV animal models and together produced 5 high-profile manuscripts. The Kunapuli lab has great expertise in platelet-mediated thrombosis and pioneered discovery of GIRK involvement in this process. Specific inhibition of GIRK isoforms may unify targeting Afib and Stroke with a single approach.

NIH Research Projects · FY 2025 · 1994-09

RESEARCH & RELATED - OTHER PROJECT INFORMATION - PROJECT SUMMARY/ABSTRACT In this Program Project renewal application, we propose to fundamentally expand current understanding of the variable potentially functional modulations of the CB1 and CB2 cannabinoid receptors. During this current period, our work has resulted in the development of a number of key pharmacologically diverse and selective agonists and antagonists for CB1 and CB2 cannabinoid receptors. We also produced detailed information on the structures of these two receptors. Based upon the strengths of this foundational work, we now propose to develop new functionally selective tools for fine tuning CB1 function and for selectively enhancing CB2 actions in vivo. Our work will generate early candidates for the discovery and development of new therapeutic medications. In this renewal, we will elucidate the functional selectivity aspect of CB1 agonists and develop positive allosteric modulators at CB1 that selectively enhance endocannabinoid signaling. We also propose to develop highly selective CB2 agonists to enable studies of CB2 in vivo while limiting the contributions of CB1 that have been associated with undesirable side effects. Additionally, we propose to develop ligands that act as activators of CB2 while also acting as CB1 antagonists. Using such compounds in vivo may lay the groundwork for the development of medications for inflammatory and fibrotic disorders. Our goals will be accomplished through the synthesis of druggable analogs. The design of these ligands will be based on existing structures of the CB1 and CB2 receptors that were developed during the current funding period and by utilizing computational approaches. The work will require detailed molecular pharmacology aimed at studying the signaling of novel compounds accompanied by targeted mutations in CB1 and CB2 to confirm mechanistic underpinnings of pharmacological divergences in signaling. The most efficient novel compounds will be assayed using in vivo approaches aimed at exploring potential therapeutic value. The overall project will provide foundational information on cannabinoid receptor signaling and serve as a basis for the future development of rationally designed, mechanism-based therapeutic medications.

Other NSERC · FY 2024

Terahertz, 6G, Network-on-Chip, Plasmonic Antennas, Graphene, Spectrum, Reinforcement Learning