University Of New Mexico

NIH Research Projects · FY 2025 · 2022-08

: Alcohol use disorder (AUD) is a significant public health problem, yet treatments demonstrate only modest efficacy, likely due to the the profound phenotypic heterogeneity of AUD. In order to improve the efficacy of AUD treatments, it is imperative to better characterize this heterogeneity which may, in turn, elucidate clearer treatment targets for precision medicine approaches. This likely requires shifting conceptualizations of AUD away from clinical description and towards etiologic mechanisms, an approach embodied by the goals of some modern conceputalizations of AUD, such as the Addiction Research Domain Criteria (AARDoC) and Addictions Neuroclinical Assessment (ANA). However, current research suggests that AARDoC and ANA suffer from important shortcomings, including limited clinical efficiency, and may therefore benefit from further development, refinement, and validation. To address these shortcomings, the proposed project aims to (a) empirically test the models articulated by modern conceptual AUD etiological frameworks, including the ANA, and (b) derive a mechanism-based computerized adaptive test (CAT) assessment of AUD developed using principles of objective test construction and community-based participatory research strategies. First, a candidate set of self-report items indexing 13 etiologic domains articulated by the Etiologic, Theory-Based, Ontogenetic Hierarchical (ETOH) framework of AUD mechanisms, which serves as a recent extension of AARDoC/ANA, will be derived from the literature and two rounds of cognitive interviews will be used to refine the item set among a representative group of participants (N = 50) with hazardous or harmful alcohol use. Next, items will be administered to a combined community and clinical sample (N = 1,200) to empirically test the structure of items and determine the best-fitting model. Item response theory will then be used to calibrate the items for the purpose of building a CAT for each of the domains identified (e.g., reward, cognitive control, negative emotionality). Using the refined and calibrated item set and domain-specific CATs, data will be collected from an additional independent sample of heavy drinkers (N = 100). Ecological momentary assessment over 14 days and a follow-up assessment will also be conducted with the goal of evaluating the psychometric properties of the CATs in ecologically valid contexts and over time. Specifically, to determine if the domain-specific CATs demonstrate validity (e.g., convergent, discriminant, predictive) and reliability (e.g., test-retest). All research aims will be conducted alongside and in consultation with individuals with lived experience of AUD to ensure the measure is acceptable, feasible, and adequately contextualized. This project is consistent with NIAAA's Strategic Plan, specifically Goal 1 (Identify mechanisms of alcohol-related pathology) and Goal 2 (Improve diagnosis and tracking of AUD). The resulting measure also has the potential to support progress towards Goal 4 (Develop and improve treatments for AUD) by facilitating the assessment of mechanisms that may serve as viable targets in AUD treatments, including behavioral and pharmacological interventions.

NIH Research Projects · FY 2025 · 2022-06

SUMMARY Transmission of human schistosome parasites depends on availability of suitable aquatic snail intermediate hosts. If no schistosome-transmitting snails are present, or snails no longer support schistosome development, there will be no schistosomiasis. Developing snail-targeted genetic control programs has long been advocated, but hampered by the lack of necessary genetic knowledge and effective germline manipulation tools. The objective of this project is to exploit our recently developed genetic and genomic resources, in combination with application of emerging powerful technologies, to address fundamental mechanisms of schistosome resistance of snails in two snail-schistosome systems, Biomphalaria spp.–Schistosoma mansoni and Bulinus spp.–S. haematobium, which are involved in transmission of intestinal and urogenital schistosomiasis, respectively. The two snail-schistosome systems are responsible for approximately 99% of human schistosomiasis transmission in the world. We propose to employ two new snail models, Bi. glabrata– S. mansoni and Bu. truncatus–S. haematobium to represent the two systems for the study. In Aim 1, we will apply whole genome sequencing (WGS) to scan single nucleotide polymorphisms (SNPs) of individual recombination inbred lines (RILs) to generate high-resolution genetic maps of schistosome resistance in juvenile and adult Bi. glabrata, the best-studied snail model of schistosomiasis. The RILs have been bred from our new model that consists of two homozygous lines of Bi. glabrata, one fully susceptible to, and the other completely resistant to, S. mansoni, the most important causative agent of intestinal schistosomiasis. In Aim 2, we will employ RNA sequencing (RNAseq) to investigate differential expression and allelic variation of genome-wide genes using our newly developed genetic resources (i.e., RIL snails and their two homozygous parent snails). A comprehensive analysis of RNAseq data coupled with genes identified in the fine resistance loci will lead to accurate identification of small number of resistance candidates, which will be used for subsequent studies, including genetic variation of resistance genes in natural populations in endemic areas proposed in this aim. In Aim 3, we will use a combined approach of functional and comparative genomics to identify syntenic regions between Bi. glabrata and Bu. truncatus and reveal the genomic basis of schistosome resistance in Bu. truncatus, an intermediate host of S. haematobium. Paradoxically, S. haematobium, despite being the most abundant of all schistosome species infecting people, has received very little attention with respect to its interactions with its bulinid snail hosts. In Aim 4, we will utilize RNAi (RNA interference) and CRISPR (clustered regularly interspaced short palindromic repeats) to functionally verify the candidate genes affecting snail compatibility to S. mansoni or S. haematobium. This study will lead to a much deeper understanding of schistosome resistance in Bi. glabrata, provide the first molecular insight into the genomic basis underpinning competence of bulinid snails to schistosome, and help develop more effective and novel methods for controlling schistosomiasis.

NIH Research Projects · FY 2026 · 2022-04

ABSTRACT The Undergraduate Research Initiative for Student Enhancement (U-RISE) at the University of New Mexico is a two-year program that integrates mentoring, research, and academics to train and prepare undergraduate students from underrepresented minorities (URM) and groups (URG) for doctoral programs (and ultimately careers) in biomedical research. Specifically, the U-RISE at UNM goals are to: 1) Increase the number of students from biomedically-relevant majors involved in research programs as undergraduates, 2) Encourage URM students to enter graduate research degree programs, and 3) Recruit and prepare U-RISE scholars for graduate school and research careers through an integrated mentoring and training program that will enhance academic and research skills. Key measurable outcomes include that 100% of U-RISE scholars will graduate within two years of joining U-RISE and at least 80% of our scholars will matriculate into doctoral programs (PhD or MD/PhD) within 3 years of graduation. Thirty scholars will be recruited over five years from the Departments of Biochemistry & Molecular Biology, Biology, Chemistry & Chemical Biology, Mathematics & Statistics, Physics, Psychology and the School of Engineering at the end of their sophomore years. Criteria for scholar selection will include, but are not limited to GPA (typically > 3.2), underrepresented status, and a desire to pursue a career in biomedical research. Other factors that would suggest that a student would excel in the program, graduate school and beyond, will also be considered. Students will participate in authentic research experiences with one of our 26 mentors from across the UNM campus. Required and elective courses will strengthen writing and quantitative/computational skills and provide training in methods to enhance data rigor and reproducibility, and responsible conduct in research. Professional development training and mentoring will contribute to scholar success. At the same time, the U- RISE at UNM program will improve undergraduate experiences overall through improvements in advising, curriculum, and dissemination of information about opportunities for undergraduate research and graduate school. Evaluation of the U-RISE scholars, mentors, and pack leaders will be performed each year and student success will be followed for fifteen years after graduation to determine the success of each program element, to identify areas for improvement, and to disseminate information about successes and challenges for the program.

NIH Research Projects · FY 2026 · 2022-02

PROJECT SUMMARY/ABSTRACT Fetal Alcohol Spectrum Disorders are a set of major morphological, neurobiological, and cognitive abnormalities in offspring exposed to alcohol in utero. A common cognitive manifestation of alcohol exposure during neural development in humans, and in animal models of prenatal alcohol exposure (PAE), are deficits in spatial learning and memory. In moderate PAE, which accounts for the most common and underestimated form of PAE, spatial deficits are marked by an inability to accurately discriminate between spatial locations or recall previously learned spatial relationships. Systems-level monitoring of neural populations in the hippocampal formation has unraveled a critical role for this circuit in the generation of spatial memories and their subsequent recall. The well-characterized spatial and oscillatory organization of hippocampal spiking is thought to play a critical role in these processes. The long-term goal of our research program is to identify the neurobiological mechanisms of spatial learning and memory impairments after moderate PAE. While the behavioral phenotype of altered spatial behavior after moderate PAE is well established, there is still a critical need to identify the systems-level mechanisms including the neural circuitry and brain dynamics involved in such deficits. A multi-level understanding framework for the study of spatial impairments is essential in developing a complete understanding of the impact of PAE on nervous system function and toward the development of targeted interventions. The overall objective of this proposal is to identify these systems-level alterations by monitoring large ensembles of hippocampal neurons and their oscillatory dynamics during both spatial learning and memory and in “offline periods” of rest and sleep. In two aims, we will test our central hypothesis that PAE induced perturbations to spatial learning and memory are a consequence of a loss in the expression of distinct hippocampal ensemble codes for place and their synchronization and organization within hippocampal oscillations during rest and sleep. The aims of this R01 represent a critical step towards our long-term goal of identifying the neurobiological mechanisms of spatial learning and memory deficits after moderate PAE but will also provide critical insight into the systems-level impact of moderate PAE on hippocampal population activity. The relationship between hippocampal population activity and spatial learning and memory is well established in a wide range of species including humans. Thus, this proposal has the potential to provide a novel scientific framework whereby new strategies for interventions can be developed and tested in preclinical models but can also be developed for human patient populations.

NIH Research Projects · FY 2025 · 2021-09

Chronic pain and opioid use disorder (OUD) are major public health problems. Despite the alarming increases in opioid misuse and OUD, few integrated treatments target both chronic pain and OUD. Integrated holistic treatments are desperately needed that simultaneously address pain and opioid use, the fundamental causes of pain and OUD, and that focus on whole person functioning and well-being among individuals with chronic pain and opioid misuse/OUD. The University of New Mexico (UNM) Integrative Management of chronic Pain and Opioid use disorder for Whole Recovery (IMPOWR) Center will take an integrated and holistic approach to improving the lives of patients with chronic pain and opioid misuse/OUD via tailored intervention approaches. We will explicitly target increasing quality of life and engagement in valued activities and tailoring interventions to meet the needs of patient populations. The approaches proposed in our IMPOWR Center will directly target whole person functioning and well-being among individuals with chronic pain and misuse/OUD. Our goals are to develop, test, and implement scalable, generalizable, and sustainable provider- and patient-level interventions that are focused on improving functioning and can be delivered in a range of health care settings. To maximize impact, we have established a Consultation Board and a Scientific Advisory Board (including experts in chronic pain, opioid misuse/OUD, and implementation science), and aim to build a workforce of researchers and providers devoted to ameliorating chronic pain and OUD via training and mentoring. All Center projects will embrace principles of team science, implementation science, economic evaluation, and open science. Consistent with our patient-centered approach, assessment of opioid use and chronic pain will be complemented with measures of psychosocial functioning and other important life domains, including engagement in valued activities and quality of life. Projects will include economic evaluation to measure cost-effectiveness of our interventions from a societal perspective. Specific research projects will test the effectiveness, mechanisms, and implementation of an integrated psychosocial treatment for chronic pain and OUD among individuals receiving buprenorphine from outpatient OUD treatment clinics, and will use community-based participatory research methods to develop an implementation intervention for screening and brief intervention of chronic pain and OUD among American Indian/Alaska Native patients in primary care settings. Pilot projects focused on chronic pain and OUD will be selected by our Consultation Board. The UNM IMPOWR Center is committed to data harmonization, sharing of study resources, and provider training to enhance the reach, effectiveness, adoption, implementation, and maintenance of evidence-based treatments for chronic pain and OUD.

NIH Research Projects · FY 2025 · 2021-08

The goal of this study is to test a multilevel approach to reduce adverse consequences of the pandemic with disparate impacts on Latin American and Black immigrants and refugees by observing and implementing three nested levels of intervention: 1) an efficacious 6-month peer advocacy and mutual learning model (Refugee and Immigrant Well-being Project, RIWP); 2) engagement with community-based organizations (CBOs); and 3) structural policy changes enacted in response to the pandemic, such as a state disaster relief proposal for Latin American newcomer families and expanded statewide health insurance coverage. This community-based participatory research (CBPR) study builds on a long-standing collaboration with five community-based organizations (CBOs) that focus on mental health, education, legal issues, and system change efforts to improve the well-being of Latin American and African immigrants and refugees. By including 240 Latin American and 60 African newcomers recruited from CBO partners who are randomly assigned to treatment-as- usual CBO involvement or the RIWP intervention and a random sample comparison group of 600 Latin American newcomers, this mixed methods longitudinal waitlist control group design study with seven time points over 36 months will test the effectiveness of the RIWP intervention and engagement with CBOs to reduce psychological distress, daily stressors, and economic precarity and increase protective factors (social support, awareness of/access to resources, English proficiency, cultural connectedness, and mental health service use). This study will also test the ability of the RIWP intervention and engagement with CBOs to increase access to the direct benefits of structural interventions (local/state relief-related policies) for Latin American and Black immigrants and refugees. Mechanisms of intervention effectiveness will be explored by testing mediating relationships between primary outcomes and protective factors. We will also track local/state policy changes and obtain preliminary quantitative estimates of effects of these structural interventions on psychological distress, stressors, and economic precarity using propensity score matching. Qualitative interview data from a purposive subsample of participants and CBO staff will enable additional exploration of mechanisms of change, the effects of policy interventions on individuals, how CBOs contribute to enacting policies and helping people benefit from them, and the context of RIWP implementation at each site. This research is innovative and significant because it employs cutting-edge research design and intervention strategies to advance the science of multilevel mental health interventions that aim to understand and address mental health disparities that have been highlighted and exacerbated by the pandemic. Thus, this study will contribute not only to reducing the disparate adverse mental health, behavioral, and socioeconomic consequences of the pandemic but also to our ability to eliminate mental health disparities among Latin American and Black populations.

NIH Research Projects · FY 2025 · 2021-07

Chemicals produced by living systems, or natural products, have had a tremendous impact on human health. For example, nearly one third of all small molecule drugs approved by a regulatory agency over the past nearly four decades have been natural products or derivatives of natural products, including over 70% of antibiotics and 40% of anticancer drugs [1]. While very useful molecules have been identified among the hundreds of thousands of natural products that have been characterized to date, genome sequencing efforts over the past decade and a half have revealed that we have only characterized the products of a small fraction of the biosynthetic pathways that exist in nature. The products of these pathways have the potential to greatly impact the diagnosis and treatment of disease, and it is critical that we develop new approaches to accelerate the identification and characterization of new natural products and natural product-like compounds. Towards this critical need, my group focuses on the ribosomally synthesized and post-translationally modified peptide (RiPP) class of natural products [2], and the enzymes involved in their biosynthesis. Unique among natural product biosynthetic pathways, the substrate of the RiPP biosynthetic enzymes is a genetically encoded precursor peptide. This feature of the substrates allows for deep mutational analysis, not just of the enzymes, but of their substrates as well. We will develop a platform for high throughput examination of the substrate selectivity and activity of RiPP biosynthetic enzymes based on yeast or bacterial surface display, fluorescence activated cell sorting, and next generation sequencing. Using this platform and gene libraries encoding substrate variants we will study the substrate scope of these enzymes, and how that scope relates to the sequence of the native substrate of the enzymes. Additionally, we will perform deep mutational analysis of the enzymes to identify contributions to substrate recognition and selectivity. These studies will provide us with a deeper understanding of how these enzymes function. With this deeper understanding, we will be able to use these enzymes as tools to generate large libraries of natural product-like compounds that can be screened to identify those with useful biological activities more efficiently than current natural product discovery approaches.

NIH Research Projects · FY 2025 · 2021-07

This Mentored Patient-Oriented Research Career Development application (K23) will provide protected time for Dr. Margo Hurlocker to become an independent researcher at the University of New Mexico (UNM) and Center on Alcohol, Substance use, And Addictions (CASAA). Her goal is to develop the expertise to integrate and test implementation strategies within clinical trial designs to improve the treatment delivery system and client engagement in addiction and other behavioral treatment programs. As a first step in developing expertise in addiction implementation science, the candidate proposes an original, mentored research study focused on replacing the comprehensive assessment with an evidence-based intervention (Motivational Interviewing [MI]) during a client’s initial contact with an addiction treatment program to improve client entry, engagement and retention. Addiction treatment programs have some of the highest premature dropout rates and approximately 44% of clients drop out after the intake assessment. The assessment-based intake may contribute to the high rates of client dropout given the emphasis on gathering information rather than exploring client reasons for seeking treatment. This study builds on a large body of literature supporting MI as a prelude to other evidence- based treatments to facilitate treatment engagement, by using an effectiveness-implementation hybrid design to (1) examine the clinical utility of MI at intake on client’s entry and engagement in treatment, and (2) use a mixed-methods approach to evaluate treatment personnel’s’ perspectives of implementation feasibility. Also, in-treatment factors (readiness to change; working alliance) are examined as putative mechanisms of engagement-related outcomes given pre-treatment factors tend to account for a small amount of variance in client dropout. This mentored study will offer hands-on training to help the candidate develop the expertise to establish her own independent addiction research program. With the guidance of her mentorship team, Dr. Hurlocker’s training plan and mentored study are integrated and will promote a comprehensive skill set in the following areas: (1) conducting clinical effectiveness research in addiction treatment programs (Theresa Moyers & Barbara McCrady; UNM), (2) implementation theory and application (Geoffrey Curran; UAMS & Kamilla Venner; UNM), (3) implementation process evaluations (Theresa Moyers; UNM & Geoffrey Curran; UAMS), and (4) advanced quantitative analyses of client and provider data (Katie Witkiewitz; UNM). All mentors will also assist Dr. Hurlocker in grant preparations and submissions throughout the award period. In addition to training at CASAA, Dr. Hurlocker will complete substantive coursework with the Institute for Implementation Science Scholars at Washington University in St. Louis and advanced quantitative coursework at UNM. Collectively, Dr. Hurlocker’s training goals and mentored study are in line with NIDA’s attention to 1) the development of innovative methods to improve the healthcare delivery system, and 2) the identification of in-treatment mechanisms that can promote patient engagement (e.g., PAR-18-007).

NIH Research Projects · FY 2025 · 2021-05

Language treatments for chronic aphasia are not restorative, and the psychosocial and economic impacts of aphasia are devastating. Knowledge of modifiable brain targets has not been harnessed to catalyze meaningful treatment outcomes. Transcranial direct current stimulation (tDCS) allows systematic investigations of the effects of brain target engagement. tDCS investigations aim to restore a left hemisphere bias for language processing. tDCS has strong clinical translational potential, but the diffuse current flow it delivers to the stroke brain and uncontrolled cortical dosage limits inferential precision. Although tDCS could be used to shape hemispheric contributions to language and investigate target engagement, methodological approaches so far have not employed it for that purpose, preventing vertical progress in aphasia treatment development. Both aphasia and tDCS research are lacking data on meaningful language outcomes and treatment-induced brain changes. There is a critical need for rigorous investigations of treatments capable of coaxing spared brain areas into adaptive participation for functional improvements. Failure to meet this need means that millions of people with aphasia will have little hope for easing of disability burden. The long-term goal is to optimize aphasia recovery with clinically translatable brain-based approaches. The overall objective of this project is to determine how to induce functional language improvement and adaptive changes to spared eloquent language cortex. The central hypothesis is that functional language outcomes for people with chronic aphasia will be enhanced when treatment focuses on normalizing language processing bias to the left hemisphere. The rationale is that identifying behavioral and adjunctive treatments that engage brain targets will allow optimization of treatment parameters and facilitate the development of novel and personalized approaches to move beyond the status quo and towards precision neurorehabilitation. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Demonstrate the enhancing effect of targeted right hemisphere modulation; and 2) Measure normalization of brain activity following treatment. Under the first aim, language treatment will be paired with active or sham HD-tDCS to inhibit right inferior frontal right gyrus (pars triangularis), after which gains in narrative and naming will be measured and the two groups compared. Under the second aim, changes in EEG measures of brain function will be characterized and related to narrative and naming outcomes. This contribution will be significant because it is expected to have broad application to clinical populations who would benefit from treatment-induced adaptive brain reorganization. Our major innovation for this project is the pairing of a proven behavioral treatment that will recruit language networks with targeted “high-definition” tDCS (HD-tDCS) to focus inhibition and control cortical dosage to the frontal right hemisphere. These contributions will be important for the more than 2.4 million adults in the United States living with aphasia.

NIH Research Projects · FY 2024 · 2019-09

PROJECT SUMMARY: Chronic pain is common, costly, and debilitating. Opioid prescription in the treatment of chronic pain is frequent and carries a consequent risk of poor treatment outcome, as well as higher morbidity and mortality in a clinically significant number of patients, particularly those who meet criteria for opioid dependence. Despite the alarming increases in prescription opiate misuse and opioid use disorder (OUD) nationally in the United States, there are few treatment options available that target both pain-related interference and OUD among patients with chronic pain. In military veterans, this issue is of particular importance as numerous reports indicate frequent use of opioids in the treatment of chronic pain, as well as increasing opioid-related problems. To date, there are no evidenced-based treatment options which aim to both reduce pain interference simultaneously addressing problematic opioid use. The overall aim of the parent study (UH3DA051241) is to determine the efficacy of an integrated psychosocial treatment in veterans with chronic pain, who are taking buprenorphine for the treatment of OUD. To examine this aim, we are utilizing a multisite randomized clinical trial design to assess the efficacy of two empirically supported interventions: Acceptance and Commitment Therapy for chronic pain and Mindfulness Based Relapse Prevention for substance use and misuse. Efficacy will be assessed by examining pain interference and opioid misuse outcomes after three months of active treatment, as well as at 6 and 12 month follow-ups. Secondary outcomes, including depression, pain-related fears, and other substance use, will also be assessed at these same follow-ups. The study will also examine the relation between within- treatment changes in treatment mechanisms, including pain acceptance, engagement in values based action, and opioid craving, and changes at post- treatment and follow-up. The results of this study will directly inform treatment of patients with chronic pain and represents a significant advance in the growing and understudied problem of OUD among patients with chronic pain. In addition to addressing the question of whether the treatment is feasible, it will further examine issues of treatment mechanisms to better inform the provision of treatment. This supplement to the parent award will support finalizing recruitment, treatment, and follow-up of the sample at three Veterans Administration Healthcare System sites, and will aid in dissemination efforts.

NIH Research Projects · FY 2025 · 2018-05

Project Summary/Abstract The long-term objective of this proposal is to understand inductive and effector mechanisms of host defense in the intestinal mucosa. We use as a tool the intracellular protozoan Toxoplasma gondii, an orally acquired opportunistic pathogen inducing strong protective Th1- and IFN--based immunity and that is a significant health hazard in immunocompromised populations. Signaling through the adaptor molecule MyD88 is necessary for optimal initiation of immunity and resistance to this pathogen. While IL-1 family cytokine receptors use MyD88, the primary role of this signaling adaptor during T. gondii infection is believed to be in Toll-like receptor (TLR) signaling. Nevertheless, the particular TLR involved (TLR11/12) are not expressed in humans and indeed many other species, indicating presence of MyD88-independent pathways of immune initiation. Such pathways are also present in mice, insofar as infection of MyD88 knockout animals triggers robust, albeit delayed, Th1 responses in the intestinal mucosa. Additionally, MyD88 knockout mice can be vaccinated against lethal challenge with orally inoculated Toxoplasma. Open questions remain regarding the role of MyD88 in specific cell types and in the context of the intestine how the microbiota influences MyD88-dependent and MyD88-independent immunity during Toxoplasma infection. The central hypothesis underpinning our research is that MyD88-dependent pathways and MyD88-independent pathways work together to provide optimal immune initiation during infection. We will address this hypothesis focusing on interactions between cells of the lamina propria, Toxoplasma and the host microbiota. Using our hypothesis to guide us, we will pursue three specific aims. Aim 1: Determine the role of intestinal epithelial cells in initiation of immunity and control of Toxoplasma. Using intestinal organoids we will examine how epithelial cells respond to infection, and how this impacts responses in the lamina propria compartment. The influence of epithelial MyD88 in immunity to T. gondii will be determined. Aim 2: Identify how MyD88 impacts innate lymphoid cell (ILC) function during Toxoplasma infection. The activity of ILC, with a focus on ILC1 and ILC3, will be examined using mouse strains deficient in ILC populations and strains with deletion of MyD88 in ILC. Aim 3: Determine the influence of MyD88 expression on generation of mucosal T cell effector and memory function. The requirement for MyD88 in lamina propria T cells will be determined with regard to short term effector function and long-term memory function. The importance of this research is that it will significantly extend and deepen our understanding of mechanisms of resistance to Toxoplasma within the mucosal immune system, which is critical to understanding mucosal host defense in humans. The ultimate impact of this research is that it can be expected to identify novel parasite and host targets for promoting resistance and immunity during infection with Toxoplasma and other microbial pathogens that threaten human health.

NIH Research Projects · FY 2025 · 2017-03

PROJECT SUMMARY/ABSTRACT This grant application proposes to use the unique stationary Multi-X-ray-source Array (MXA) technology developed and applied to digital breast tomosynthesis (DBT) under our current R01 to: 1) significantly improve DBT image quality by extending the MXA technology to produce a clinically practical two-dimensional (2D) MXA and 2) demonstrate a capable and fully characterized 2D MXA DBT system to use for clinical trials under a follow-on R01 Academic–Industrial Partnership program. By the time the first film-based commercial tomosynthesis systems were developed in the 1970s, it was realized that 2D motion of the X-ray source significantly improved image quality relative to 1D motion due to better blurring of the shadows of structures both above and below the plane of interest. All existing commercial DBT systems use 1D motion because 2D mechanical motion is complicated and expensive and would significantly increase scan times which are already too long at 4 to 25 s with the 1D motion-based systems. Compare this to mammography, where it is preferred to keep scan times under 2 s to minimize patient-motion artifacts. Extending MXA technology to make 2D breast tomosynthesis practical – by meeting scan time constraints – will provide superior performance compared with all commercial breast tomosynthesis systems on the market today, while at the same time decreasing system size and cost. The net result would be a significant increase in the capability of DBT systems and a broadening of their availability to bring better care to more people sooner. The Specific Aims of this application are: Aim 1. Use modeling and experiments to design the 2D MXA-DBT prototype system Aim 2. Build 2D MXA DBT prototype system Aim 3. Evaluate performance of 2D MXA DBT prototype system

NIH Research Projects · FY 2025 · 2015-09

PROJECT SUMMARY Life course theory emphasizes that aging is a trajectory that starts early in life, and as such, individual heterogeneity in aging is rooted in a lifetime of health exposures and the environments in which we live. This perspective is critical for understanding the nature and modifiability of health inequalities among the aged. However, it has been extraordinarily difficult to put life course perspectives into practice, owing to the long timeframes necessary to study humans and the difficulty of operationalizing relevant features of human environments. We propose that these problems can be rectified by studying an underused model system, chimpanzees. This research extends a longitudinal study aimed at investigating the biology of aging in chimpanzees, one of our closest living relatives and a critical link for reconstructing how the human aging process evolved. This close evolutionary relationship results in genetic and physiological similarities that are not represented by common laboratory animal models. Chimpanzees are socially-complex and long-lived, meaning that they are particularly well suited to study how environmental factors such as the chronic burden of infection, social support, and social inequality yield health effects across a lifetime. In our first funding period, we validated a robust toolkit of non-invasive biomarkers of health and aging and used longitudinal sampling of chimpanzees to establish how the chimpanzee aging process compares with humans. In the renewal period, we build on those successes by addressing the multidimensionality of our longitudinal health data. Aim 1 will extend the longitudinal health monitoring and biosampling of our original sample and increase the sample to a total of 350 wild and 200 free-ranging chimpanzees. We will also develop accessible resources for comparative aging research. Aim 2 will examine the hypothesis that the cumulative burden of infection across life is a significant determinant of individual heterogeneity in aging. The immune system plays a pivotal role in the aging process and has complex feedbacks on other aspects of senescence. Yet, the long lifespans of humans evolved in environments where infectious challenges to the immune system were persistent. In wild chimpanzees, we can study these dynamics in a system without medical intervention and where other age- related pathologies are rare. Aim 3 builds upon Aim 2 by examining the hypothesis that social processes modify aging trajectories. We are particularly interested in understanding the mechanisms by which social support and status from early adulthood, when they are first established, contribute to later life health disparities, and whether these impacts can be further modified by age-related shifts in social behavior. Chimpanzees in our study populations have been closely observed for most or all of their adult lives, providing a rare opportunity to apply objective, detailed social histories to the study of aging in the absence of major lifestyle factors that complicate human studies.

NIH Research Projects · FY 2026 · 2012-05

Sc histosomiasis is one of the world's most common neglected tropical diseases, currently infecting over 200 million people, with 90% of cases occurring in tropical Africa. The involvement of freshwater snails as vectors imparts considerable stability to the schistosome life cycle because snails support the prolific production by asexual reproduction of cercariae, the infective stage of the parasite for people. Efforts thus far to control schistosomes in snails have had but limited success. Our work's overall goal is to identify innovative new ways to interrupt the development and transmission of Schistosoma mansoni in its obligatory Biomphalaria snail hosts, especially in the context of the Lake Victoria basin. Rather than to attempt to suppress large snail populations across broad endemic areas, our approach is to find specific ways to target infected snails and the larval stages of schistosomes living within them . Our field studies also constantly remind us of the impact a warming c limate may have on vector snails and the schistosomes developing within them. Building on both lab- and field-based discoveries made in our ongoing funding period, we propose the following new aims: Aim 1. We seek to learn if immune responses we have shown to be relevant to resistance in a lab model, the Neotropical snail B. glabrata and S. mansoni, are also at play in African Biomphalaria taxa in western Kenya. The transcriptomics and other studies we propose will identify novel characteristics of the responses of African snails to schistosome infection and how snail responses to S. mansoni might be affected by warming c limates. Aim 2. We aim to characterize the means whereby larval trematodes, especially ubiquitously common cattle-transmitted amphistomes, suppress and supplant the development of S. mansoni sporocysts in African Biomphalaria taxa . We will use a combination of in vivo and in vitro approaches coupled with transcriptomics, proteomics and metabolomics techniques to address this issue. Aim 3. We hypothesize that shore-dwelling B. sudanica suffers constant exposure to many different trematode species, including S. mansoni, and have developed a generalist immune strategy featuring tolerance to minimize trematode impact. In contrast, a close relative, B. choanomphala, lives in a deepwater refugium from infection, and we predict will show diminished immune responsiveness and lack of tolerance responses upon challenge with trematodes. Our aims all seek to characterize novel ways to interfere with the development of schistosome larval development in snai ls, build a two-way bridge between lab and field studies and will enable us to continue a 30+ year collaboration between biologists at UNM and the Kenya Medical Research Institute, emphasizing training of young scientists in medical malacology. RELEVANCE (See instructions): Schistosomiasis is one of the world's most common neglected tropical diseases. Its resilience is partly due to the reliance of schistosome parasites on freshwater snail vectors that support the production of prolific numbers of human-infective cercariae. We propose to explo it immune resistance mechanisms in snails and the means whereby competing larval trematodes interfere with larval schistosomes in snails to develop needed new means to control transmission of schistosome parasites to people in sub-Saharan Africa. P ROJ EC / P E R FO R M AN C E SI T E(S) (if ad ditional space is need ed , use ProjecU Performance Site Format

NIH Research Projects · FY 2025 · 2010-07

This application requests five more years of support for a highly successful training program directed and run at the University of New Mexico (UNM) Center on Alcohol, Substance use, And Addictions (CASAA) since 2010. CASAA is an interdisciplinary center devoted to prevention, treatment, mechanisms of behavior change, and implementation research on alcohol, substance use, and other addictive behaviors, as well as comorbid conditions. The NIAAA-funded T32 training program at CASAA is supported by faculty within the UNM Department of Psychology and faculty mentors within six other Departments and Colleges. In the last 14 years, the program has trained 42 pre- and postdoctoral trainees for independent careers in alcohol research, nearly all of whom have continued in research careers. This renewal requests ongoing support for four predoctoral trainees, drawn from the UNM Department of Psychology, and three postdoctoral trainees from disciplines relevant to the goals of the training program, such as psychology, sociology, economics, education, addiction medicine, psychiatry, social work, public health, epidemiology, neuroscience, and pharmacy. The training program prepares future scientists to conduct rigorous alcohol research across a range of areas including evidence-based treatment, mechanisms of behavior change, precision medicine, comorbidity and the individual- and system-level factors related to alcohol use, polysubstance use, and other addictive behaviors, technology-based interventions, and implementation science; and draws on several new conceptual and methodological approaches with the goal of reducing the public health burden of alcohol use disorder. For example, trainees address questions such as: What types of interventions are more or less effective in supporting recovery from alcohol use disorder across individuals (e.g., with respect to comorbidities), and, equally important, what specific aspects of treatment account for their effectiveness? Eleven core faculty serve as the primary and/or secondary preceptors for trainees. Core faculty have strong records of mentorship, research, and funding on precision medicine and mechanisms of behavior change, prevention and treatment, technology-based interventions, comorbidity, and implementation science. The 16 contributing faculty serve as secondary or supporting preceptors and bring complementary expertise in neuroscience, quantitative and qualitative methods, public health, and education as well as provide content expertise and opportunities for secondary research experiences. The CASAA T32 training program, which will be formally and informally evaluated annually by trainees, mentors, and an external advisory board, provides a rigorous curriculum and individualized mentoring plans in responsible conduct of alcohol research, transparency and reproducibility, mechanisms of behavior change, implementation science, NIH grant writing, and advanced quantitative and qualitative methodologies.

NIH Research Projects · FY 2026 · 2005-09

Project Summary/Abstract The University of New Mexico Postbaccalaureate Research and Education Program (PREP @ UNM) is a biomedical research training program, focused on individuals from minority and historically underrepresented groups who intend to enter a Ph.D. program. Based on a series of defined objectives we will: recruit well- qualified under-represented scholars to our program; create and realize individualized development plans to provide laboratory research experience and tailored skills for academic, professional, and personal growth; provide support for successful application of scholars to Ph.D. programs and careers in the biomedical research workforce; and investigate the parameters impacting graduate school retention and utilize these data to improve graduate training at UNM. We anticipate that this training will notably increase the number of well- trained under-represented individuals in the sciences.

NIH Research Projects · FY 2026 · 1998-06

There exist fundamental gaps in the knowledge base regarding the mechanism of Mo cofactor sulfurase C- terminal (MOSC) domain enzymes and how they differ from sulfite oxidase (SO) family enzymes, how DMSO reductase (DMSOR) family enzyme geometric structure contributes to the wide range of complex chemical transformations catalyzed, and how the electronic structure of pyranopterin dithiolene (PDT) component of the Mo cofactor (Moco) modulates Mo-PDT covalency and contributes to catalysis in all pyranopterin Mo enzymes. Our long-term goal is to understand how molybdoenzyme geometric and electronic structure contribute to reactivity and function to provide a positive impact on the quality of human health. Our overall objective is to determine the mechanism of molybdoenzymes critical to human health and how the PDT contributes to catalysis by employing a combined spectroscopic approach augmented by detailed bonding, spectroscopic, and reaction coordinate computations. The central hypothesis is that specific geometric and electronic structure modifications of protein-bound Moco define the unique enzymatic reactions catalyzed. The rationale for this research is that a comprehensive understanding of mARC mediated transformations, the role of DMSOR family enzymes in supporting virulence and the transformation of small molecules into metabolites, and the complex interplay between Mo and the PDT ligand in all molybdoenzymes will provide new insights into disease states and have a positive impact on human health. We will test our central hypothesis in order to accomplish the objectives of this proposal through the successful pursuit of three Specific Aims 1) Understand mARC and related MOSC family enzymes, 2) Determine active site contributions to catalysis in DMSOR family enzymes, 3) Determine PDT electronic structure contributions to reactivity. The proposed research is innovative in its approach because it 1) utilizes a combination of spectroscopy, electronic structure computations, and kinetic data to interrogate proteins that lack additional redox chromophores, coupled with variants and models that have not been studied in detail, to derive insight into mechanism and protein scaffold constraints on geometry, 2) directly addresses prior challenges related to spectroscopically probing the PDT using new small molecule analogs that possess a PDT ligand and 3) develops S K-edge HERFD X-ray emission (HERFD-XES) as a probe of S→Mo charge transfer states. This has led to new insight into long-standing questions in the molybdoenzyme field, effectively opening new horizons for future work in this area. The proposed research is significant since it will reveal how active site electronic and geometric structure control reactivity related to the role of molybdoenzymes in disease states, drug metabolism, and gut microbial metabolism.