George Washington University

NIH Research Projects · FY 2025 · 2005-04

Abstract Chronic neuropathic pain (CNP) is a maladaptive pathological process that is poorly understood and a condition for which no effective therapies exist. It is largely recognized that neuroinflammation significantly contributes to the development of chronic pain, however the mechanisms are not well understood. A unifying mechanism through which pathological inflammation contributes to the development of chronic pain is by being a key mediator of neuropathology and maladaptive plasticity in brain regions critical for processing somatosensory information such as the somatosensory cortex (S1). The overarching hypothesis to be tested in this competitive renewal is that strategies designed to mitigate pathological neuroinflammation will be therapeutic for spinal cord injury (SCI)-Pain by promoting neurorepair and reducing maladaptive supraspinal plasticity. The studies proposed in this application are based upon extensive published and preliminary data demonstrating diverging roles for TNFR (TNFR1 and TNFR2) signaling and sex differences in the development and resolution of CNP in SCI and peripheral nerve injury (CCI) models. The overarching goals of our competitive renewal are to better understand mechanisms of CNP and to develop therapies that are effective in both women and men. The lack of understanding of neuron-immune cell interactions that lead to the development or resolution of chronic pain is the overarching scientific premise to this application. Our scientific premise and hypotheses will be tested in the following Specific Aims. Specific Aim1: Interrogate the mechanisms through which TNFR2 signaling mitigates neuroinflammation in CNP in males and females. Specific Aim 2: Interrogate the divergent roles for TNFR signaling in the development and resolution of CNP and maladaptive plasticity in males and females. Specific Aim 3: Interrogate the intersection between TNFR1 and ERβ in females and mechanisms whereby inhibiting ERβ in females renders them “male-like” with respect to therapies for CNP.

NIH Research Projects · FY 2026 · 1998-04

PROJECT SUMMARY/ABSTRACT The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal- Fetal Medicine Units (MFMU) Network was created in 1986 to conduct clinical research studies in obstetrics and perinatal medicine. The MFMU Network, consisting of a number of major academic clinical centers, a data coordinating center (DCC), and the NICHD, will serve as the first-line infrastructure for implementing multi-site obstetric clinical trials and observational studies. Research studies conducted within the MFMU Network will be aimed at reducing maternal morbidity and mortality related to pregnancy, reducing fetal and infant morbidity and mortality related to preterm birth and fetal growth abnormalities, and expanding the evidence on therapeutic products used during pregnancy and lactation. To fulfill this mission, the MFMU Network plans to conduct 5-10 new studies. The MFMU Network structure allows studies to be completed in a more rigorous and reproducible fashion and more efficiently than individual multi-center projects. The overall purpose of the DCC is to make sure that the studies are designed to minimize bias, are conducted using rigorous protocols and procedures, and the results analyzed and interpreted appropriately to ensure the validity of the conclusions. The aims of the DCC are to provide scientific and biostatistical expertise through collaborations with Network and non-Network investigators on study design, conduct, analysis and reporting of clinical studies. The DCC will conduct safety and interim analyses for the Data and Safety Monitoring Board, collaborate with investigators on statistical analyses and the dissemination of study results, and share datasets and resources. The DCC will provide a flexible data management system and collaborate with investigators on the conduct and monitoring of each study including creation of study documents, training, and reporting to the Steering Committee, NIH, other committees and/or working groups, as well as the Food and Drug Administration for any studies under an IND/IDE. Lastly, the DCC will coordinate communication through both private and public websites, and provide the logistical and administrative support to the overall Network organization necessary to run efficient and productive studies. Through effective organization, communication, and logistical, technical and scientific support, the DCC will continue to provide the framework for the MFMU Network to address the key scientific questions in obstetrics, obstetric pharmacology, and lactation clinical practice.

NIH Research Projects · FY 2024 · 1992-07

Project Summary/Abstract (max. 30 lines) Loss of corneal sensory nerves develops secondary to herpes infections, stroke, or trauma; treatments are often only partially successful and lead to suffering and vision loss. The long-term objective of our research is to identify the factors that permit the corneal epithelium to reform a stable barrier after trauma so we can intervene to prevent corneal erosions from forming. Our studies of the cornea have recently focused on the intraepithelial corneal sensory nerves (ICNs) which consist of the intraepithelial corneal basal nerves (ICBNs) and the intraepithelial corneal nerve terminals (ICNTs). Mitomycin C (MMC) applied topically at the time of debridement injury acts as a neuroprotective agent. Corneal epithelial and resident dendritic cells phagocytose axonal mitochondria (aMito) from severed axons after injury. Apical cell desquamation, ICN growth and ICNT shedding are under diurnal control. We hypothesize that the ocular surface barrier and the extent of corneal tissue damage in response to injury and irritants varies with the time of day. We will test this hypothesis in Aim A by answering the following questions: 1. Does shedding of the ICNTs and the desquamation of squames occur spontaneously when lights turn on or does it persist in the dark? 2. Do differences in the corneal barrier and ICN density in the resting and active phase in the mouse impact the extent of damage done to the cornea and signaling by the ICNs to the trigeminal ganglion in response to injury and after exposure to ocular irritants The daily shedding and severing the ICNs leads to accumulation of aMito within corneal epithelial cell lysosomes followed by their degradation via transmitophagy; by contrast to retinal pigment epithelial (RPE) cells, the mechanisms that regulate phagocytosis of axonal debris in the corneal epithelium are not known. Data from our lab and others lead us to hypothesize that corneal epithelial cells internalize aMito via LC3B associated phagocytosis (LAP) and, after internalization, corneal epithelial cells regulate whether aMito undergo transmitophagy or are retained in their cytoplasm to function metabolically. We test this hypothesis in Aim B by answering the following questions: 1. Is phagocytosis of aMito and severed axons by corneal epithelial cells mediated by LAP? 2. Are functional aMito retained in the cytoplasm of epithelial cells after being transferred from axons into corneal epithelial cells during homeostasis and in response to injury? The experiments proposed use quantitative in vitro and in vivo cellular and molecular approaches to answer these questions. The knowledge gained from these studies will not only inform clinicians about the optimal time of day to deliver treatments for ocular surface disorders, they will also clarify the role that mitochondrial transfer has on enhancing wound recovery after injury in the cornea.