Howard University

NIH Research Projects · FY 2025 · 2022-08

Project Summary: Triple-negative breast cancer (TNBC) accounts for approximately 15% of invasive breast cancers and is associated with aggressive tumor biology, poor prognosis, resistance, visceral metastases and earlier disease recurrence. TNBC is more common in younger women than in older women and in African- American and Hispanic women. Platinum-based drugs showed higher sensitivity in TNBC compared to non- TNBC patients and recently there has been a renewed interest for platinum therapy in TNBC, especially combination of carboplatin with paclitaxel (PTX). Sacituzumab govitecan is made up of an anti–Trop-2 antibody linked to the chemotherapy drug (SN-38) and was cleared by the FDA for TNBC patients who have undergone at least two prior chemotherapies. The FDA granted an accelerated approval for the immunotherapy drug atezolizumab in combination with chemotherapy (nab-paclitaxel) for the treatment of TNBC (for tumors positive for PD-L1). Thus chemotherapy is important in the therapeutic management of TNBC even in the advent of immunotherapy and targeted therapy. However, chemotherapies are known to cause fatal peripheral neuropathy in addition to poor response, metastasis, relapse and development of multidrug resistance. The goal of this application is the development of multifunctional targeted nanoparticles capable of achieving better outcomes for TNBC patients: (a) targeted delivery of large doses of multiple drugs into cancer cells (per a single biorecognition event compared to a single immunotargeted drug (e.g. sacituzumab govitecan-hziy)) to maximize therapeutic effects while reducing systemic toxicity (off target toxicity); (b) EGFR-receptor targeted nanoparticles that promote intracellular drug delivery and release and which can bypass multidrug resistant protein (p-glycoprotein) which mediates efflux of drug molecules; (c) capable of long circulation without being sequestered into the liver. EGFR is overexpressed by TNBC and literature is replete with examples of the use of cetuximab in therapy by targeting EFGR. We hypothesize that the development of biodegradable polymeric nanotechnology platform containing carboplatin and paclitaxel in the core and using cetuximab (tagged on nanoparticle surface) as a targeting moiety will improve TNBC patients’ outcomes, unlike repeated chemotherapy cycles with high doses of cytotoxic drugs. We hypothesize that the dual-loaded multifunctional targeted nanoparticles will be active in vitro and show in vivo efficacy in mouse xenograft models of TNBC positive tumors. Aim #1: Fabrication of polymeric dye-loaded and-paclitaxel and carboplatin-loaded stealth hydrolysable crosslinked cetuximab surface-targeted polylactide (PLL) nanoparticles. Aim #2: Characterization of anti-EGFR mAb (cetuximab) surface-targeted-PLL-nanoparticles containing carboplatin and paclitaxel in the core. Aim #3: Biodistribution and efficacy studies in tumor-bearing mice. This work will bring to bear the combined power of chemotherapeutic agents, molecular targeted therapy and nanotechnology to overcome EGFR positive TNBC resistance and improve efficacy with minimal toxicity.

NIH Research Projects · FY 2025 · 2022-07

Project Summary Molecular & Genetic Problem: Lipid-induced hepatic insulin resistance is due to diacylglyceride (DAG)-induced protein kinase C epsilon (PKCε) activation leading to inhibition of insulin receptor tyrosine kinase [4, 5]. However, nonobese hyperandrogenic (HA) female mice displayed androgen-specific hepatic insulin resistance indicating a lipid-independent pathogenic mechanism [3]. Additionally, high fructose diets (HFrD) compared to high fat diets (HFD) display differing mechanisms of insulin resistance, where high fructose impairs glucokinase and glycogen synthase but high fat lowers p-AKT [6]. Ketohexokinase (KHK, also known as liver fructokinase) is required for HFrD-induced metabolic dysfunction [7]. The Overall Aim is to establish that differing causes of insulin resistance display crosstalk between cellular, molecular, and genetic mechanisms. I will develop 3 mouse models of hepatic insulin resistance: high androgen (HA)-induced, HFD-induced, and HFrD-induced. Using various hepatic specific knockout (KO) mice to eliminate the function of certain pathways (androgen receptor (AR-KO), ketohexokinase (KHK-KO), and protein kinase C (PKC-KO)), I will examine the intersecting pathogenic mechanisms unique to each of the three insulin resistant models. Expected Outcome: I hypothesize that each model of insulin resistance (HA, HFD, and HFrD) will contain its own unique mechanistic aspect with varying aspects of crosstalk. Thus, suggesting the movement towards targeted therapeutic interventions based on the type of insulin resistance.

NIH Research Projects · FY 2026 · 2022-05

PROJECT SUMMARY Traumatic brain injury (TBI) represents a major public health concern in the United States. TBI can result in long-term neurological complications, including neurodegeneration, behavioral dysfunction, depression and epilepsy that seriously affect patient quality-of-life. Brain glucose utilization has been found decreased in 60% of patients with chronic TBI and is one of the prognostic indicators for the long-term outcome of TBI. Both animal and human studies have identified that the neurovascular uncoupling between cerebral blood flow (CBF) and brain tissue energy demands is a key factor for cerebral metabolic crisis in the TBI brain. The neurovascular uncoupling results in energy mismatch that disrupts normal neuroglial function and arrests repairing process. Despite numerous clinical trials on potential therapies, there is no U.S. Food and Drug Administration approved drug therapy for the treatment of TBI. One of the reason clinical trials failed is due to the inability that can accurately evaluate the region-specific perturbations of brain glucose metabolism and determine if a treatment can restore neurovascular coupling in the TBI brain. Existent glucose measuring techniques, including microdialysis, continuing blood glucose monitoring, spectroscopy, or positron emission tomography (PET) which uses tracer radioisotopes, provide insufficient resolution to determine region-specific glucose utilization in the brain. In this proposal, we determine to assess the utility of a novel MRI-based Chemical Exchange Saturation Transfer (CEST) imaging, to provide the needed high-resolution for measuring region-specific metabolism for TBI. The glucose detecting CEST MRI (glucoCEST) measures brain glucose by detecting the exchangeable proton signals of glucose without using radioisotopes and generates glucose mapping in a resolution >100 times higher than PET scans. Our preliminary and published data have demonstrated that glucoCEST may be feasible to detect the delayed hypometabolism of diffuse TBI in rats. We propose to combine high-resolution glucoCEST and the Dynamic Contrast Enhanced (DCE) perfusion MRI for concomitant CBF measurements to identify the neurovascular coupling state following TBI over time. Our aims are designed to (1) Identify the contrast mechanism of in vivo glucoCEST in the TBI brain to enhance the sensitivity and specificity of glucoCEST with advanced acquisition scheme and analytical models, (2) Characterize perturbations in brain glucose metabolism and perfusion deficits in the TBI brain, and (3) Demonstrate the potential application of the dual-modality CEST-DCE MRI to noninvasively monitor the treatment effects of a clinically-recommended intervention for TBI. Overall, these studies will provide a strong technical and scientific foundation to move the field forward in utilization of advanced MRI for personalized care in the clinical arena and determine the best treatment strategy for the brain injured patients.

NIH Research Projects · FY 2026 · 2021-09

Project Summary Traumatic brain injury is a significant cause of morbidity and mortality in the United States, yet there is no approved therapy for this injury. Although several therapies and procedures have been deemed successful for TBI treatment in preclinical research studies, many of these successes did not translate to human studies. One way to examine this challenge is to investigate the methodological variances in the associated literature. This proposal aims to use experimental methods and outcomes used in traumatic brain injury (TBI) therapy papers to create a metric to compare the methodological variance between multiple species by following three aims: 1. Training Phase 1: Establish the Brain Injury Knowledge Ontology (BIKO), a standardized ontology to define experimental design parameters and outcomes. 2. Training Phase 1: Create a knowledge base, BIKO base, of experimental design parameters (methods) and scientific claims (results) from the TBI treatment discovery literature. 3. Training Phase 2: Compare experimental differences hypothesized to lead to distinct outcomes between and across multiple species in TBI studies/literature using the BIKO. Upon completion, this project will provide a clearer understanding of past preclinical TBI therapy success and how it aligns to clinical outcomes to accelerate the discovery of successful therapies for TBI in human patients.

NIH Research Projects · FY 2025 · 2021-09

Project Summary: Although the absolute risk of violence among persons with serious mental illnesses (SMI) is small, young people experiencing early psychosis are a subgroup at highest violence risk. Violence is a public health issue that contributes to health disparities experienced by adults with schizophrenia, including caregiver burden, social isolation, and incarceration and subsequent early mortality. Cognitive behavioral therapy (CBT) for psychosis and similar behavioral interventions have had efficacy in reducing impairment and improving functioning among young adults with early psychosis. However, no identified studies have explored using a behavioral intervention to reduce violence among young adults with early psychosis. In this application, Dr. Stephanie Rolin proposes a comprehensive path towards becoming an independent physician investigator creating and adapting evidence-based approaches to assess and reduce violence risk. Specifically, this proposal follows the CDC’s Map of Adaptation, a model for adapting evidence-based interventions (EBI), to adapt and evaluate the feasibility of an early intervention services (EIS)-specific CBT- based intervention to reduce violence with proposed targets consistent with the transdiagnostic nature of Research Domain Criteria (RDoC). This research will occur at OnTrackNY, the largest EIS program in the United States; OnTrackNY has provided evidence-based coordinated specialty care to over 1,800 individuals at more than 20 clinics in New York State. First, Dr. Rolin will conduct individual semi-structured interviews with EIS clients who have engaged in recent violent behavior (n=20) and clinicians who have worked with EIS clients who have engaged in violent behavior (n=10). These interviews will use the Theory of Planned Behavior to identify key areas of an existing CBT model called PICASSO (which has shown efficacy in reducing violence) that require adaptation for the EIS setting. Next, Dr. Rolin will adapt the PICASSO model for the EIS setting in an open pilot trial, through an iterative process that utilizes mixed methods assessment. Finally, Dr. Rolin will evaluate the intervention’s feasibility through a pilot RCT. To further her long-term career goal of becoming an independent physician-investigator focused on creating and adapting EBI to reduce violence risk, Dr Rolin will pursue training in the following four areas: (1) qualitative research including mixed methods; (2) psychosocial intervention adaptation; (3) psychotherapy clinical trials; and (4) grant writing. The product of this study will be an R01 of a large RCT to test the feasibility of the first EBI of CBT to reduce violence in the EIS setting. Overall, this award will ensure Dr. Rolin’s successful transition to an independent physician investigator studying the assessment and prevention of violence among adults with SMI.

NIH Research Projects · FY 2025 · 2020-12

ABSTRACT There is substantial ethnic and racial inequity in the burden of social adversities across life span, and disparities in several adult chronic diseases can be traced to social inequalities experienced in childhood. Social adversities such as poverty, harsh parenting, neighborhood disorganization, family instability, and parental incarceration are particularly pervasive in inner-city, African American (AA) populations; and can have substantial impact on biological processes that put them at risk for chronic stress disorders (e.g. posttraumatic stress disorder, PTSD) and metabolic diseases. Previously, we observed that olfactory bulb (OB) volumes were substantially reduced in AA adults who developed PTSD following severe childhood adversities, compared to those with similar exposures who did not develop PTSD, which is congruent with animal studies showing that maternal deprivation reduced OB size. Yet how these social exposures become translated into chronic health disorders, is unclear. Epigenetic factors (i.e. modifications to the genome that are not changes in nucleotide sequence) have been posited to play critical roles in mediating the impact of environmental exposures on health, due to their influence on developmental plasticity and long-term functional biology. Our proposed study builds upon our R21 study in inner-city AA populations which revealed that Growth Arrest Specific 5 (GAS5), a non-coding RNA (lncRNA) likely plays an epigenetic role as a decoy, diverting glucocorticoids from binding to glucocorticoid response elements (GRE) in the promoter regions of genes that respond to glucocorticoids and preventing downstream molecular and physiological effects. African Americans with elevated GAS5 levels, had larger OB volumes, lower afternoon cortisol levels and lower sympathetic arousal independent of burden of neighborhood disorder and perceived social stress and racial discrimination. However, our studies also revealed that social connectedness and Daily Spiritual Experience Scale also moderated a broad spectrum of stress responsive behaviors (e.g. perceived stress, affect, sleep disruptions, risk taking, and resilience), thereby providing a strong justification to investigate genome-wide epigenomic mechanisms of response to social adversities. As a result, we propose a 5-year prospective study involving genome-wide noncoding RNA profiling of 300 AA with dimensional differences in childhood social adversities. Our Specific Aims are: (1) conduct baseline microRNA (miRNA), lncRNA and mRNA profiling in olfactory neurons (ON) of AA cohorts to examine associations between noncoding RNA (ncRNA) and childhood social adversities; (2) quantify baseline associations between ncRNA levels, perceived social stress and racial discrimination, social connectedness, spiritual experience scale, and both behavioral and neurophysiologic measures of stress; and (3) investigate mediational roles of ncRNA on the predictive influences of cumulative exposures to neighborhood stress, poverty, social stress, perceived discrimination and other social disadvantages on 12-month trajectory in stress response behaviors. Our overarching hypothesis is that interactions between miRNA and lncRNA will partially mediate effects of these adverse social contexts (e.g. poverty, neighborhood disorganization, family instability, and parental incarceration) on biological processes related to stress response ( e.g. GR signaling, immune signaling, circadian molecular alterations, and elevated sympathetic tone) and stress responsive behaviors (perceived stress, psychiatric, sleep disruptions, risk taking, and resilience). This project is innovative in using non-invasively derived ON to investigate intraneuronal epigenetic mechanisms in a prospective design, and in use of microscopy to explore intraneuronal interactions between glucocorticoids, GR, miRNA and lncRNA at nano-resolution. Results of this study will provide evidence for the role that ncRNA play in mediating the effects social adversities on chronic diseases, highlight epigenomic signature of resilience and produce epigenomic hotspots for treatment intervention.

NIH Research Projects · FY 2026 · 2014-05

ABSTRACT Sickle Cell Disease (SCD), an inherited blood disorder, affects approximately 100,000 individuals in the U.S. and millions more globally. Interestingly, SCD and Sickle Cell Trait (SCT) appear to protect against HIV-1 infection, with patients showing lower infection rates and slower disease progression. Despite these observations, the underlying mechanisms remain poorly understood. Our proposed study aims to elucidate the role of trained immunity (TI) in this antiviral response. We hypothesize that products of RBC hemolysis, including HbS, induce the antiviral state in non-infected monocytes facilitating the establishment of TI and long-term protection against HIV-1 in patients with SCD. We further hypothesize that SCT individuals might also develop an antiviral response and TI-mediated protection, as SCT erythrocytes can undergo sickling and hemolysis. In Specific Aim 1, we will investigate the TI profile and antiviral response triggers in SCD. We will evaluate the TI in PBMCs and human monocyte-derived macrophages (MDM) obtained from SCD and SCD HIV-1+ patients and compare them to HIV- 1+ and healthy controls. We will also extend this analysis to mice exposed to hemolytic products. In Specific Aim 2, we will evaluate the antiviral response and TI establishment in previously identified SCT individuals from the MACS/WIHS combined cohort study (MWCCS). In Specific Aim 3, we will analyze molecular mechanisms of HIV-1 restriction and HIV-2 infection in SCD and SCT. We will use SCD, SCT and control PBMCs for ex vivo infection with HIV-2 and HIV-1. We will extend this analysis in SCD mice by developing EcoHIV-2 expression vector, with the ectotrophic MLV envelope in place of HIV-2 envelope. We will compare acute EcoHIV-2 and EcoHIV-1 infection in SCD and SCT mice. The proposed research will further elucidate the molecular basis of HIV-1 inhibition in the settings of SCD and SCT.

NIH Research Projects · FY 2026 · 1997-09

OVERALL PROJECT ABSTRACT The Howard University Research Centers in Minority Institutions (HU RCMI) program has a continuing interest in developing a better understanding of the unique parameters associated with minority health and resolving mechanisms of health disparities which is a critical component of Howard’s institutional research mission and is an abiding commitment to the communities it serves. This renewal application recognizes the critical role of research in the implementation of Howard’s commitment to further serve its surrounding communities and will enhance Howard’s capacity for basic biomedical, population science, and clinical research by improving the quality of scientific inquiry through partnerships with community-based organizations and by expanding the cadre of productive investigators at Howard. To accomplish these goals, the HU RCMI will continue its investigator development initiative, which has the capacity to fast-track junior faculty and early-stage investigators to the level of successful and productive scientists. We will also provide a selection of state-of- the-art infrastructure resources (computational biology & bioinformatics, health/clinical informatics, proteomics, and imaging) – to support faculty research efforts and incorporate enhanced support for data science efforts. These initiatives and resources will be combined with a continuation of long-term relationships with surrounding community-based organizations that serve as conduits to ensure that the needs and interests of the community are represented in the university’s research agenda. These community connections also serve as a source of participants in Howard’s human subjects research and as conduits for disseminating to the community results obtained from HU research projects. Moreover, the HU RCMI will support three rigorous research projects addressing health disparities experienced by African Americans in the areas of ischemic stroke, hypertensive disorders of pregnancy among black women, and urinary incontinence experienced by African American and Hispanic women living in the Washington, DC area. These three research projects represent efforts in the thematic areas of basic biomedical, population science, and clinical research, respectively. Additionally, the HU RCMI Program in partnership with the Department of Anatomy and Office of the Provost will recruit to Howard a senior faculty-level data science investigator whose research experience is primarily in biomedical and neuroscience data with an emphasis on minority health and health disparities. The entire HU RCMI program and each of its components will be subjected to annual evaluation by an outside and independent evaluator. The proposed HU RCMI program activities will enable Howard to reach and maintain a critical level of minority health and health disparities research.