University Of California, San Diego

NSF Awards · FY 2024 · 2024-01

Terabit-per-second data rates will enable next-generation wireless cellular applications, including extended reality, holography, haptic feedback, and wireless cognition. These applications provide, in part, the means to create an immersive experience for work, education, and healthcare which helps to bridge the gap in experience between in-person interaction and video telephony. Achieving the high data rates, though, requires going to higher radio frequency bands than are currently used for cellular communications. In the last five years, cellular communication has embraced the lower millimeter wave spectrum, which refers to radio frequencies from about 25 GHz to 100 GHz. Indeed, millimeter wave communication has become one of the defining features of fifth generation cellular communication systems. Going to terabit-per-second data rates will require higher bandwidths that are available above 100 GHz, in what is known as the sub-THz band. This collaborative project establishes fundamentals that will help realize sub-THz communication and drive the future of wireless technology. It develops new hardware and algorithms that help to create the required high data rate communication links to serve the applications highlighted above. For example, it develops technology that helps sub-THz communication signals better go around obstacles, by instrumenting the environment with smart reflective surfaces and reconfigurable antenna arrays. The results of the project will contribute to the development of new wireless technologies that are beneficial for personal communication, safety applications and industrial deployments. Industry impact and technology transfer will occur through frequent communication with the partners of the sixth generation North Carolina program. The project will lead to more undergraduate and graduate students with expertise on new and important technologies for wireless communications. Sub-THz Augmented Routing and Transmission for 6G is a collaboration among experts in wireless communications at North Carolina State University (NC State) and Yonsei University (YSU). It addresses the design of reflective surfaces and reconfigurable arrays for multiple-input multiple-output (MIMO) communication at sub-THz frequencies. It devises methods for configuring the beams formed or reflected from those arrays in a way that routes around obstacles. It creates algorithms that exploit new levels of reconfigurability in the arrays to obtain higher throughput and more robust communications. Finally, it results in the creation of joint real-time hardware (H/W) and software (S/W) testbeds for sub-THz communications. The uniqueness of this project lies in the multi-domain approach for improving sub-THz communications. The intellectual merit will occur in several directions. (a) Intelligent reflective surfaces constructed from state-of-the-art meta-materials / meta-devices. (b) Reconfigurable antenna arrays with adaptable structures that are mechanically and electrically controlled. (c) Directional-beam-based initial access and beam routing algorithms that leverage channel map information. (d) Models of reconfigurable antennas arrays and performance limits of those arrays. (e) Algorithms that leverage true time delays to reconfigure those arrays to support high bandwidths. (f) A suite of evaluation scenarios that test the developed hardware and algorithms. The immediate impact will be to identify the most relevant approaches for enabling large arrays for communication and reflective applications, as well as algorithms that leverage those arrays to enhance communication at sub-THz frequencies. The long-term impact will be in the development and realization of sub-THz communication as part of 6G wireless communications. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2024-01

ABSTRACT Current therapeutics, including the biologics, improve management of arthritic joints but often do not adequately address associated pain, suggesting multiple mechanisms. Delivery of antibodies/immune complexes in serum from a K/BxN mouse to a normal mouse yields a persistent, but reversible joint inflammation accompanied by early onset pain that persists long after resolution of inflammation. In the inflammatory phase, allodynia and the conditioned place preference respond to anti-inflammatory drugs and drugs that block spinal sensitization, while in the post-inflammatory phase, the pain phenotype responds to only to the latter agents. This profile is accompanied by changes in joint innervation, DRG and dorsal horn biology, revealing a transition over weeks in both sexes from an inflammatory to a polyneuropathic pain phenotype. The origin of this ongoing traffic and the appearance of a post-inflammatory pain phase in the preclinical rodent model reflects a major change in the phenotypic expression of channels and receptors within the DRG. Among the changes generated by inflammation and nerve injury are concurrent, time-variant, increases in nociceptive afferent expression of sodium channels (e.g., NaV 1.3,1.7,1.8,1.9) and down regulation of potassium channels (e.g., Kv1.4), changes which yield increased afferent excitability and ectopic activity. Here we will utilize the CRISPR-dCas9 system coupled with transcriptional activation domains or transcriptional repression domains to enable either activation or repression of the above genes epigenetically to systematically study their roles in modulating pain states. We have already extensively characterized the efficacy, duration, and safety profiles of epigenetic repression of NaV1.7 in DRG primary afferents via intrathecal (IT) AAV9 (CRISPR)-dCas9 delivery. Our work has shown, in vitro and in vivo after intrathecal delivery, titer dependent reduction in DRG NaV1.7 mRNA and allodynia in murine inflammatory and polyneuropathic pain models. We propose now, using this IT AAV CRISPR-dCas9 epigenome modifying platform to focus in male and female K/BxN mice on the inflammatory and poly-neuropathic joint pain component of repressing DRG NaV 1.3, 1.7,1.8,1.9 and increasing expression of Kv 1.4-channels. We will characterize these modifications in K/BxN and K/BxN- IT AAV9 (CRISPR)-dCas9 treated male and female mice on i) DRG target expression using RNA seq/RNA-FISH; ii) K/BxN driven allodynia / aversiveness (using conditioned place preference); iii) adverse event profile; iv) ectopic activity and membrane excitability (patch clamping) in primary DRG neuronal cell cultures and v) in vivo basal and evoked afferent substance P release. These aims provide mechanistic insights into the role of. these DRG-afferent channel populations in the inflammatory and post inflammatory arthritic pain phenotype accounting for the ongoing and evoked pain phenotype. These insights into regulation of multiple DRG channels will also guide improved engineering of potential therapeutic interventions.

NSF Awards · FY 2024 · 2024-01

Future wireless networks will integrate sensing and communication functions. The sensing capabilities can come from the sensors of the devices in the network. The radio communication signal itself can also be used for sensing, especially when operating at high carrier frequencies, with high bandwidths and large antenna arrays. Examples are cellular networks supporting automated vehicles or industrial robots equipped with radar, lidar or cameras. This project advances the fundamental technologies, from a hardware and software perspective, to enable integrated sensing, learning and communication (ISLAC) wireless networks, capable of obtaining and communicating accurate information about the environment, relevant for the users and for the network operation itself. The sensing accuracy provided by these technologies is critical, both to support a given use case, and to enhance the resilience of the network, enabling a fast respond to failures or mis-configurations. The outcomes of this project will improve cellular connectivity for people and devices, by providing higher data rates, with more reliability, in a way that embraces machine learning and the wealth of sensor data also being deployed in such networks. To establish the potential of integrated sensing, learning and communication networks to enhance their own resilience, this project develops: (a) the core enabling technologies for ISLAC networks, including hardware and signal processing algorithms for joint sensing and communications; (b) mathematical tools to measure resilience accounting for the particular propagation features and network operation at millimeter wave (mmWave) and sub-Terahertz (sub-THz) bands; (c) learning strategies that exploit sensing information to improve network adaptability; and (d) user-centric algorithms that exploit sensing information to improve network autonomy and increase. The developed strategies will be evaluated using a framework based on a combination of ray tracing, experimental measurements and models that mix the digital, physical, and virtual worlds. This methodology will enable the evaluation of the developed technologies in several relevant scenarios supported by cellular networks, including automated vehicles, automated factories, and immersive reality settings. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2024-01

ABSTRACT Chimeric antigen receptor (CAR) T-cells are a revolutionary cancer treatment, with the particular benefit of generating memory T-cells that can last for years and suppress cancer relapse. CAR-expressing CD8+ T-cells have been shown to cure leukemia and other cancers in clinical trials with great success. However, many challenges remain before CAR-based immunotherapy can become widely adopted, particularly for solid tumors. A major problem is that CAR T-cells become “exhausted” or “dysfunctional” and display decreased therapeutic effectiveness when subjected to prolonged antigen stimulation in the tumor microenvironment. Elevated cytosolic calcium is associated with T-cell activation, and as such, calcium signaling activity can be used as a quantitative measure of T-cell function or dysfunction. The history of calcium signaling over short and long periods of time encodes information about the current functional capacity of the T-cell and the number of tumor cells encountered in the past, and can be used both to evaluate populations or individual clones and to select for clones resistant to exhaustion. However, imaging calcium signaling activity in vivo using traditional genetically encoded fluorescent indicators presents unique challenges with T-cells and other highly mobile cell types, especially when medium- to long-term activity tracking is required. There is currently no facile method to image calcium signals at the single-cell level over long time periods or to track calcium activity history in such a highly mobile cell population, either in vitro or in vivo. In this project, we will use several distinct varieties of photoactive fluorescent proteins coupled with a family of high-contrast bioluminescent calcium sensors to generate Optical Recorders for Calcium (ORCas) capable of reporting short-, medium-, and long-term calcium signaling histories in CAR T-cells upon repeated exposure to target tumor cells. We will additionally engineer the small molecule substrates used to time-gate history recording for improved bioavailability and cell specificity, and to diversify the wavelengths of light emitted by the bioluminescent sensor domains of these probes. The engineered ORCas will ultimately be used to (1) track the exhaustion status of CAR T-cells over long periods of repeated exposure to target tumor cells, (2) enrich exhaustion-resistant populations of CAR T-cells from CRISPR knockout libraries, and (3) quantitatively benchmark the exhaustion resistance of CAR T-cell clones. These probes will additionally be validated in CAR T-cells in vivo in a subcutaneous mouse tumor model. Ultimately, we anticipate that ORCas will be the first of a broad new class of genetically-encoded probes capable of recording specific biochemical signal history non-invasively in many disease models and therapeutic interventions.

NIH Research Projects · FY 2025 · 2024-01

PROJECT SUMMARY OVERALL The overall objective of the proposed UCSD Learning Health Systems (LHS) Center is to provide didactic and experiential training in learning health systems science to clinicians and other scientists from diverse backgrounds. The three cores of the Center – Administrative Core, Research and Education Core, and Research and Data Analysis Core – will operate as inter-dependent parts of the Center infrastructure to support the professional development of scientists to conduct research that accelerates progress towards an integrated learning health system. By design, the Center’s LHS infrastructure and workflow present holistic opportunities for LHS Scientists to interact with their sponsors, with their cohort, and other member of the LHS community. A LHS research project funded in the Center will also provide LHS Scientists a learning opportunity encompassing the full circle of developing, executing, managing, and reporting a research project as an embedded scientist. The proposed LHS Center will enhance diversity of both the LHS Scientists as well as patients who will benefit from LHS interventions in a minimum of three safety net health systems, UCSD and two federally qualified health centers, El Centro Regional Medical Center (ECRMC) and Family Health Centers of San Diego (FHCSD), that serve disproportionally underserved and minoritized populations. Multi-channel outreach efforts will cover underrepresented minority faculty and scientists both within and outside of the UCSD health sciences programs. Healthcare professionals including nurses and social scientists such as economists and sociologists are also eligible. The proposed Center has assembled faculty members representing multiple disciplines, gender, race, and age. Many of them specialize in health equity and are national leaders in reducing racial disparities in access to health services. All of them are engaged in research efforts that are well aligned with AHRQ/PCORI’s priorities. Their projects offer LHS Scientists experiential education opportunities that will be highly beneficial in preparation for their own research project. The proposed Center aims to (1) mentor and train clinicians and other scientists in competencies of learning health systems, organizational transformation, hypothesis generation and testing, data management and analysis, patient and stakeholder engagement, and how to apply research insights to address health system priorities in real world practice workflow; (2) to support and train LHS Scientists in sophisticated methods of deriving study-relevant structured and unstructured data from the electronic health record system and gain competencies in mixed methods research; and (3) to facilitate bidirectional asset-based community development opportunities for implementation of learning health systems pragmatic research in resource constrained care environments with diverse and underserved populations and in academic health systems with a broad range of deep expertise.

NIH Research Projects · FY 2025 · 2024-01

Abstract Heart, Lung, Blood, and Sleep (HLBS) conditions such as heart failure, COPD, and pneumonia are among the most common causes of hospitalizations. Many of such hospitalizations are thought to be avoidable with early recognition and intervention. Today, patient-reported symptoms represent the primary means of detecting impending hospitalizations, but because symptoms are late indicators of disease, this results in days to weeks of delay in receiving care. We developed a non-contact adherence-independent longitudinal bed-sensing platform to detect early physiologic signs of impending hospitalizations before patients recognize or self-report symptoms. Preliminary results from our bed-based mechanical sensors suggest that the technology can learn patient-specific baselines during clinical stability and can recognize excursions from baseline in the early stages of developing illness. Here, we propose a milestone-based project aimed at collecting human training datasets and developing generalizable models that can recognize impending hospitalizations in the home with a focus on the underrepresented populations of San Diego and Imperial Valley counties. Doing so will encourage utilization and adoption across HLBS disease verticals and patient subpopulations.

NIH Research Projects · FY 2025 · 2023-12

Abstract Immunotherapy is a promising therapeutic strategy for many cancers. Anti-tumor immune responses are elicited against neoantigens that arise from genetic alterations within tumor cells that give rise to a repertoire of peptides that the immune system recognizes as non-self and attack, killing the tumor cells harboring them. Cancers with a high mutational load generally benefit from immune checkpoint therapy, but some solid malignancies, like pancreatic cancer, have a low mutational burden that hampers immunotherapy. One strategy to overcome this limitation is to deliver exogenous neoantigens to cancer cells. Here we propose an approach that uses the tumor penetrating peptide iRGD, to deliver neoantigens to pancreatic tumors. Unlike conventional RGD peptides, iRGD, is not only able to target and the tumor vasculature through αv integrin, but also to extravasate and penetrate tumor tissue via neuropilin-1 delivering conjugated or co-administered drugs or peptides. Pancreatic cancer long term survivors often have neoantigens that mimic common viral epitopes, suggesting the possibility that these individuals benefited from an immune response against neoantigens that mimic viral components. We posit that iRGD-mediated delivery of these antigens to pancreatic tumors will redirect pre-existing antiviral immunity against them. For this purpose, we will use peptides activating cytomegalovirus (CMV)-specific T cells. CMV is a β-herpesvirus infects >60% of the population and elicits a strong immune response accounting for >10% of all circulating CD4 and CD8 T cells. Our preliminary data show that mice latently infected with CMV containing orthotopic pancreatic tumors respond to treatment with iRGD plus CMV peptides with tumor regression associated to increased necrosis, and marked T cell infiltration. Here we propose experiments to determine in an orthotopic pancreatic tumor mouse model, what are the best neoantigens and the optimal treatment conditions for achieving long lasting tumor regression (Aim 1). We will also assess the presence of CMV specific T cells in human pancreatic tumors, a necessary step toward the eventual translatability of this approach (Aim 2).

NIH Research Projects · FY 2026 · 2023-12

Project Summary / Abstract This joint application by biosynthetic chemist Bradley Moore (UCSD/SIO) and neuroscientist Jerold Chun (SBP) is in response to the Notice of Special Interest: Promoting Mechanistic Research on Therapeutic and Other Biological Properties of Minor Cannabinoids and Terpenes recently issued by NCCIH (NOT-AT-22-027). The Moore and Chun laboratories have synergized their complimentary research efforts to address a mounting national health concern and opportunity surrounding the legalization and increased use of cannabis by millions of Americans both medicinally and recreationally. They aim to expand their new biocatalytic methods to construct rare and minor cannabinoids and analogs and to evaluate their potential therapeutic benefits in murine and human receptor assays and animal models. The successful development of new cannabinoid therapeutics depends on comprehensive pharmacological data, especially for the >110 minor phytocannabinoids. Given the paucity of functional information on them, the significance of the endocannabinoid system in the regulation and control of many critical bodily functions, and the relevant crosstalk between cannabinoid (CB) and lysophosphatidic acid (LPA) G protein-coupled receptor (GPCR) systems, we hypothesize that phytocannabinoids and/or their metabolic derivatives similarly modulate non-classical LPA receptors. Our preliminary work indicates that CBC phosphate (CBCp) engages the receptor LPA1, thereby opening new vistas for phytocannabinoid GPCR receptor biology, physiology and pathophysiology. We will test the hypothesis that phytocannabinoids and/or their metabolites modulate non-classical LPA as well as classical CB receptors to impact physiology and disease through two specific aims over the next five years. Specific aim 1 will discover, characterize, and engineer biocatalysts for the construction of structurally diverse minor cannabinoids and analogues. We will expand our preliminary results that bacterial enzymes can be used to chemoenzymatically synthesize cannabinoid molecules. Biochemical, genetic, and engineering approaches using diverse enzyme and substrate libraries will expand our ability to produce diverse cannabinoid molecules for biological evaluation. Specific aim 2 will interrogate non-classical and classical cannabinoid receptor interactions through the use of backscattering interferometry and cell-based receptor assays; and animal studies using wildtype and receptor-knockout mice that will assess normal physiological effects and pathophysiological effects previously linked to LPA signaling, including neuropathic pain (partial sciatic nerve ligation (PSNL)) and multiple sclerosis (experimental autoimmune encephalomyelitis (EAE)). These studies will reveal new insights into the minor cannabinoids and their cross-talk to lysophopholipids, which have genuine therapeutic potential.

NIH Research Projects · FY 2025 · 2023-12

ABSTRACT By the year 2050, the US population over age 65 will double and the population over age 85 will increase 5-fold. A large and increasing number of older people with schizophrenia will need more effective services. Older adults with schizophrenia are at risk for cognitive and functional decline leading to premature institutionalization. Over the past two decades, we developed Cognitive Behavioral Social Skills Training (CBSST) and established its efficacy for preventing functional decline in people with schizophrenia. In longitudinal studies, older participants with schizophrenia receiving CBSST did not improve significantly in functioning but did remain stable over 1-2 years, whereas older participants in treatment as usual and supportive contact (SC) experienced decline in functioning. CBSST is now recommended by SAMSHA as an evidence-based psychosocial intervention to prevent functional decline in middle-age to older adults with schizophrenia. Our prior work focused primarily on middle-aged adults, but our recent pilot data also showed that CBSST can prevent decline in functioning in adults with schizophrenia aged 60 or above (mean age (SD) = 65.3 (5.3)). In this late-life schizophrenia clinical trial, we also observed: (1) patients who showed larger improvement in CBSST Skills Learning showed significant improvement, not just stability, in functioning at 1-year follow-up; and (2) CBSST Skills Learning was predicted by baseline executive function. These findings suggest that CBSST Skills Learning is an important mechanism of change in functioning in CBSST and that boosting executive function could boost CBSST Skills Learning, which could improve rather than only stabilize functioning. Our group has also developed an Executive Function Training program that improves executive function but has only modest impact on functioning in mid-life adults with schizophrenia. Thus, given (1) the extensive evidence that CBSST maintains but does not improve functioning in mid- and late-life adults with schizophrenia; (2) Executive Function Training improves executive function but has limited effect on functioning; and (3) CBSST Skills Learning is associated with executive function, we propose a two-site R61/R33 to test among adults with late-life schizophrenia whether combining Executive Function Training with CBSST (E-CBSST) will result in better CBSST Skills Learning, and in turn, improve rather than only maintain functioning. If successful, we will test E-CBSST in a larger confirmatory trial and if successful E-CBSST would be the first psychosocial intervention to lead to such improvement in late-life schizophrenia. There is no doubt that stronger effective treatments for functional disability in late-life individuals living with schizophrenia would have a profound effect on patients, family members, society and the economy.

NIH Research Projects · FY 2026 · 2023-12

PROJECT SUMMARY Neurons, like other cells, respond to stressful stimuli by mounting a series of pro-survival responses. When the stress is sufficiently mild and/or transient, neurons can recover and resume apparently normal cellular and network function. This proposal builds on our recent discovery of “actinification:” a pro-survival reorganization of the neuronal actin cytoskeleton in response to the perturbed osmoregulation that occurs during stroke in vivo and NMDA receptor hyperactivation in vitro in which F-actin rapidly depolymerizes from dendritic spines and assembles into long, extremely stable filaments within the soma and dendrite. Actinification is induced by the convergence of cell swelling and calcium influx that activates inverted formin 2 (INF2). Direct manipulation of the level and activity of INF2 show that it positively regulates the induction of actinification and subsequent resistance to cell death. Our central hypothesis is that INF2- dependent actin reorganization is an essential mechanism that confers a temporary pro-survival advantage to neurons undergoing excitatory stress by protecting the somatodendritic compartment from acute damage while preserving synaptic circuitry. We propose to apply biochemistry and cell biology approaches to a) identify the molecular mechanisms that underlie INF2-dependent actinification; b) to define how actinification confers resistance to cell death and c) to characterize actinification-associated changes in synapse functionality during stress and recovery. These experiments will accelerate a fundamental understanding of pro-survival responses to stress that are specifically relevant to stroke, seizure, and brain trauma, and broadly relevant to Alzheimer’s and other chronic conditions that are exacerbated by excitotoxicity.

NIH Research Projects · FY 2026 · 2023-12

Project Summary Friedreich’s ataxia (FRDA) is a multi-systemic autosomal recessive disorder that is predominantly caused by a homozygous GAA repeat expansion mutation within the first intron of the frataxin (FXN) gene leading to a decrease of protein expression. Frataxin is a mitochondrial protein involved in iron metabolism. FRDA is characterized by ataxia, neurodegeneration, muscle weakness, and cardiomyopathy. There is no treatment for this lethal disease. We tested a new therapy for this disease consisting of wildtype (WT) hematopoietic stem and progenitor cell (HSPC) transplantation in the Y8GR mouse model of FRDA. This therapy worked beyond our expectation in FRDA completely correcting the neurologic, muscular and cardiac complications after a single infusion of HSPCs in lethally irradiated Y8GR mice. We optimized an autologous CRISPR/Cas9-mediated gene correction HSPC approach for FRDA and we are now conducting the investigational New Drug-enabling studies for the clinical translation of this approach. Addressing the mechanism of action, we previously showed that tissue rescue was at least partly mediated by transfer of frataxin from HSPC-derived microglia-like cells to diseased neurons. The exact mechanism of rescue including how microglial replacement and frataxin transfer from microglia-like cells to neurons contributes to this rescue are still unknown. Very few studies investigated the role of microglia in the pathogenesis of FRDA. We believe that the impressive response of the FXN- expressing HSPC transplant is due to, not only the transfer of FXN into neurons, but also to the rescue of the microglial phenotype. The central hypothesis is that these findings in the mouse model are translatable such that CRISPR-editing of the GAA repeat expansion in HSPCs in FRDA will lead to both functional rescue of microglia-like cells and transfer of FTX to neurons. Applying a novel cohort of induced pluripotent stem cells from FRDA patients, controls, and importantly lines created with the proposed gene editing, we find a dramatic phenotype in FRDA microglia that is corrected by editing. We will utilize novel in vitro and in vivo methods including patient-derived organoids (mini-brains) and a murine xenotransplantation model of human microglia to ascertain the microglial contribution to FRDA pathogenesis, the potential for gene editing to correct this phenotype, and the mechanisms and functional ramifications of FTX transfer to neurons from microglia. . This project is significant because it provides a human specific platform for disease modeling and validating novel therapeutic approaches and provides supporting evidence that CRISPR HPSC transplantation can be used to treat FRDA. It will also advance the understanding of microglia-neuron interactions, and open new perspectives for the treatment of neurodegenerative diseases due to mitochondrial dysfunction.

NIH Research Projects · FY 2026 · 2023-12

PROJECT SUMMARY This R01 proposal responds to “Notice of Special Interest in Research on the Health of Sexual and Gender Minority (SGM) Populations” (NOT-MD-19-001) which calls for research describing “clinical, behavioral, and social processes affecting the health of SGM individuals and their families” that will promote development of appropriate interventions to improve SGM health and fertility care. This proposal includes clinical studies of transgender individuals and the effects of androgen treatment on their reproductive health. Androgens can have significant inhibitory effects on neuroendocrine reproductive hormone secretion in both sexes, yet the mechanisms and cell types by which androgens suppress GnRH and LH pulsatile and surge secretion in females are poorly studied and remain unknown. Indeed, high levels of exogenous androgens fundamentally contribute to reproductive disruption seen in otherwise healthy women and transgender men (female sex individuals taking high levels of androgens), but the mechanisms, time course, and target neuroendocrine site(s) of action for these inhibitory androgen effects are poorly understood. Our overall hypothesis is that male levels of exogenous androgens can inhibit the female reproductive neuroendocrine axis by acting through androgen receptor (AR) in hypothalamic kisspeptin neurons to modulate endogenous LH pulse secretion and impede generation of the estrogen-generated preovulatory LH surge. We test this hypothesis in two complementary Aims that study the role of high exogenous androgens in both a clinical setting in transgender male (female sex) human subjects and corresponding transgenic female mouse models. Aim 1 investigates the effects of exogenous androgens in a clinical setting, studying transgender men taking gender affirming testosterone therapy. This clinical Aim assess the inhibitory effects and time-course of androgen treatment on a wide suite of reproductive neuroendocrine parameters, with a focus on in vivo LH pulse and LH surge secretion, coupled with analyses of menstrual cyclicity and ovarian measures. Aim 2 utilizes transgenic mice to test whether male-level androgens acting via AR specifically in kisspeptin neurons are necessary and/or sufficient for androgen inhibition of in vivo LH pulse parameters, including pulse frequency, and the estrogen-induced LH surge. This Aim also elucidates whether elevated androgen action directly in kisspeptin cells is necessary for AR inhibition of reproductive gene expression in the female brain, and uses innovative methodology to analyze androgen-induced changes in the transcriptome of specific kisspeptin neural populations in females, identifying how exogenous androgens impact these neurons to impede LH secretion. Together, these two complementary Aims will elucidate the cellular, molecular, and physiological mechanisms of androgen inhibition on female neuroendocrine reproductive hormones. This project will advance our understanding of fundamental mechanisms of androgen action in neuroendocrine control of reproduction and inform upon future clinical interventions for rescuing reproductive function in females or currently understudied SGM transgender males exposed to exogenous androgens.

NIH Research Projects · FY 2026 · 2023-12

PROJECT ABSTRACT High sedentary behavior (SB) increases risk for all-cause mortality, cardiovascular disease (CVD), cancer, and type 2 diabetes. However, mixed evidence on how much to limit SB or how to break up SB to reduce its negative health impacts has inhibited specific quantified SB guidelines The ubiquity of wearable sensors, able to collect data at fine granularity (e.g., 30Hz), enables rich, nuanced SB assessment. Computational methods to accurately quantify SB accumulation patterns (e.g., long uninterrupted bouts of SB versus fragmented SB with numerous breaks) are needed. Building on our previous work, in this project we will implement deep learning methods to derive posture-based SB measures for the widely used ActiGraph sensor from raw accelerometer (at 30 Hz granularity) or processed count outputs from hip- or wrist-worn devices across a broad range of population groups (Aims 1, 2). We will develop a deep-learned convolution neural network (CNN) bidirectional long short-term memory (Bi-LSTM) model. We will use extensive training and held-out testing to reduce overfitting and improve accuracy and reproducibility on future samples. To develop our models, we will leverage data from seven existing separately funded studies comprising 6390 unique free-living individuals with hip- or wrist-accelerometer data (>200,000 hours of device wear), and concurrent criterion posture assessment. We will apply deep transfer learning, novel in SB research, which exploits the basic neural architecture of an existing model, and finetunes it for a new cohort or application. Deep transfer learning can markedly reduce computational complexity and avoids the need for large criterion datasets. We will apply our new classifiers to quantify SB from hip- and wrist-worn ActiGraphs for participants from the NHANES and WHISH Studies (N= 42,496), and evaluate cross-sectional and longitudinal associations between SB patterns and cardiometabolic health in youth and adults (Aim 3). Enabling use of a single device, i.e., the ActiGraph, to obtain posture-based SB metrics, as well as energy-expenditure based physical activity measures, will obviate the need for multiple devices, and improve participant compliance. Our publicly available algorithms and accurate SB metrics will advance SB research, allowing researchers to transfer our models to other cohorts, enabling specific quantified public health SB guidelines (similar to physical activity guidelines) and laying the foundation for future development of self- monitoring tools for clinicians or interventionists to personalize SB goals for their patients, and facilitate SB change.

NIH Research Projects · FY 2026 · 2023-12

Project Summary Nucleus-forming bacteriophages (phages) are a recently discovered class of lytic phages that protect their genome by encapsulating it in a nucleus-like protein shell (phage nucleus). The goal of the proposed research is to determine whether the unique properties of nucleus-forming phages make them advantageous therapies for human Pseudomonas aeruginosa infections. ΦKZ and ΦPA3 are nucleus-forming phages that infect P. aeruginosa and demonstrate the ability to selectively localize proteins to their phage nucleus and exclude others, including DNA-targeting bacterial phage defense proteins. Preliminary data show that ΦKZ gp69 is a conserved protein in P. aeruginosa nucleus-forming phages and plays a key role in mediating selective protein trafficking into the phage nucleus. This research will determine the structure of gp69 in complex with other nuclear shell-associated proteins, the mechanism by which gp69 mediates protein transport into the phage nucleus, and other factors that facilitate transport into the phage nucleus. Furthermore, this research will determine the motifs that signal a protein to be imported into the phage nucleus, how those motifs differ between P. aeruginosa infecting phage, and the competitive advantages selective protein import imparts on nucleus-forming phages. Lastly, resistance to phages is known to select for costly evolutionary trade-offs in the host bacterium. This research will determine how pathogenicity and antibiotic sensitivity are altered in P. aeruginosa resistant to nucleus-forming phages. Together, the results of this study will provide crucial information for the development of nucleus-forming phage therapeutics.

NIH Research Projects · FY 2026 · 2023-11

Project Summary/Abstract As a neurocritical care physician, I have a strong background in neurophysiology, clinical neurology, and critical care; as a post-graduate student who studied neuroscience, I have a background in cognitive neuroscience. I also have a research passion for neuroscience topics such as sleep and cognition, including how to optimize or enhance cognition. Within this K-23 proposal, I merge these clinical and research passions and outline a thorough five-year curriculum with hands-on and didactic education to address deficiencies and to achieve my goal of improving outcomes in older adults with acute brain injury (ABI). I have assembled a mentorship team consisting of experts in sleep, aging, delirium, critical care, geriatric neuropsychology (including Alzheimer’s disease and related dementias; ADRD) and biostatistics. The proposed research plan seeks to understand the impact of sleep disruption in the Neurological Intensive Care Unit (ICU) on older patients with ABI. In current practice, the neurocritical care community performs frequent serial neurological examinations (“neurochecks”) in an effort to monitor patients for neurological deterioration following ABI. Many neurocritical patients are older and/or cognitively fragile, and delirium is common. Although ICU delirium is multifaceted, frequent neurochecks may represent a modifiable risk factor if we can better understand the risks and benefits of various neurocheck frequencies. My hypothesis is that the sleep interruption we induce in the Neurological ICU in our patients following ABI may actually negatively impact their post-ICU recovery because of the known associations between: 1) sleep disruption and delirium, 2) aging and delirium, 3) aging and dementia such as ADRD, and 4) sleep and cognition. It is possible that sleep interruption during critical illness exerts an effect on new or progressive dementia in part through delirium. In this context, this innovative, impactful, carefully considered, and feasible proposal will first [Aim 1] randomize patients with acute spontaneous intracerebral hemorrhage (ICH) to either hourly (Q1) or every-other-hour (Q2) neurochecks and evaluate the impact of neurocheck frequency on delirium duration. Second [Aim 2], to better understand the effect of Q1 versus Q2 on sleep, non-sedated patients without structural brain injury will be randomized to either Q1 or Q2 neurochecks with evaluation of objective and subjective sleep characteristics. Lastly [Aim 3], longer-term cognitive outcomes will be investigated in patients with ICH randomized to Q1 versus Q2 neurochecks with the goal of identifying whether hourly neurochecks increase the risk for dementia/ADRD. We have designed our studies with a particular emphasis on human subjects’ protections and developed a protocol that is well within standard of care at institutions across the USA. This grant will be instrumental to my vision as it will provide me with the protected time for training that I require to attain first-rate patient-oriented research skills. Ultimately, I endeavor to become an independent R01-funded neurocritical care physician scientist focused on improving the neurocognitive health of ICU patients at risk for cognitive decline including ADRD.

NIH Research Projects · FY 2026 · 2023-11

SUMMARY CD8 T cells are a critical component of the immune response to intracellular infections and malignancies given their ability to directly kill target cells in tissues. After the resolution of an acute infection, a small proportion of antigen-specific T cells persists as long-lived memory cells and provides protection upon re-infection. Memory CD8 T cell populations show a spectrum of phenotypic, functional, and recirculation capacities as well as the potential for secondary memory formation. Memory T cells have traditionally been studied in blood and secondary lymphoid organs, with central memory cells found recirculating between the blood and lymphoid tissues and effector memory T cells found in blood and tissues. It is now understood that long-lived, tissue- resident memory CD8 T cells (TRM) comprise a significant portion of the memory immune response, mediating host protection at sites of potential reinfection and, in some cases, causing immunopathology associated with chronic infection and autoimmunity. We find that the transition of immune cells from a itinerant, recirculating pattern to established residence in a specific tissue is accompanied by significant changes in gene expression and genome accessibility. These T cell adaptations to the unique tissue environment mediate formation, survival, and function of TRM populations. The transcriptional repressor Hic1 has recently been identified as a critical regulator of the small intestine (SI) TRM population generated in response to acute viral infection. These findings raise many new questions, such as (1) Which cues and cellular interactions regulate these adaptations? (2) How are transcriptional circuits controlling tissue residency, immune function, and memory potential integrated? And (3) What are the specific targets of Hic1 and its mechanisms of action? In this proposal, we will address the underlying mechanisms of Hic1 activity in establishing TRM, its role in the transcriptional network governing SI residency, and its importance in TRM secondary memory potential. We propose the following: Aim 1: Define the role of Hic1 in the regulation of TRM differentiation and maintenance and the signals that induce Hic1 expression in infection; Aim 2: Elucidate the role of Hic1 in the transcriptional network governing CD8 T residency in the small intestine, and Aim 3: Determine the tissue-specific regulation of TRM fates and the potential for proliferation and contribution to memory responses. These studies will inform efforts to induce “tissue-tailored” immune responses to improve vaccine efficacy.

NSF Awards · FY 2023 · 2023-11

Understanding evolution is fundamental to understanding life on earth. Evolution also creates some of the greatest challenges to human health. Viruses, bacteria, fungi, and cancer cells all evolve resistance to xenobiotics. These xenobiotics are molecules that are not found naturally but that influence evolution in the natural world. This project aims to create new theory and experiments to understand xenobiotic evolution. The results of this project would have applications across many different fields such as bacteria resistant to antibiotics, malaria parasites resistant to antimalarial drugs, tumor cells resistant to cancer drugs, plants resistant to herbicides, and insects resistant to insecticides. The award provides support to train STEM graduate students that will eventually become part of the workforce. The project also provides research opportunities for undergraduates and develops new educational games that teach K-12 students about science, using xenobiotic evolution as an example. The main goal of this project is to discover novel aspects of xenobiotic adaptation that result from the interactions between mutations and gene amplifications. The project examines the complex, nonlinear evolutionary pathways that lead to xenobiotic adaptation in the context of antibiotic resistance evolution induced by Rifampin in E. coli. Mathematically, the project would model resistance evolution as a function of plasmid copy number with the use of a stochastic process that accounts for tunneling rates and spatial structures of the community of evolving cells. The project makes use of an incoherent feed forward loop that gives synthetic control for providing variation in plasmid copy numbers in cells while keeping biochemical levels constant. Synthetic biology experiments are designed with a view to parametrizing the models under development and exploring the effects of specific parameters that have been indicated as important by the model. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2023 · 2023-11

Evolutionary theory for asexual populations seeks to understand how and why genetic change happens in a variety of contexts, from unicellular organisms over generations, to aging and disease of multicellular organisms within the lifespan of a single individual (somatic evolution). While the principles of mutant evolution in homogeneous populations are well-understood and are commonly part of textbooks, they do not directly apply to any realistic population with a spatial, hierarchical structure (such as stem cells that maintain the tissue and more differentiated cells that perform tissue function). These features are, however, a common theme of cell dynamics in tissues of higher organisms, as well as microbial populations such as biofilm forming bacteria, which are also characterized by both spatial and hierarchical structure (cell sub-populations with different specializations). This research project will extend fundamental laws of evolution to be applicable across a much greater variety of biological systems. The mathematical theory will be applied to experimental data that follow the evolution of cells in a mouse model of Rhabdomyosarcoma, which is a pediatric cancer. Finally, the project will develop a new mentoring program that facilitates interactions between students and professors, geared especially towards underrepresented students. A large mathematical literature exists about mutant spread and invasion, focusing on measures such as the mutant fixation probability or the time to mutant fixation in constant populations, as well as mutant load in growing populations. Scaling laws of evolutionary dynamics have been derived, including the equilibrium population density in spatial models, the rate of stochastic tunneling (double-mutant generation from a minority of single mutants), and the mutant content in expanding colonies. In various biological scenarios, however, cells and organisms evolve in more complex settings than those traditionally considered by evolutionary theory. Of particular importance are spatially structured, hierarchically organized cell populations that are regulated by signaling mechanisms. Examples include tissues consisting of stem and more differentiated cells, solid tumors, and biofilms containing bacterial cells with specialized functions. A comprehensive evolutionary theory for such population structures currently does not exist. This project seeks to mathematically define evolutionary scaling laws for spatially structured populations that are hierarchically organized and contain regulatory feedback loops that control cell fate decisions. This will be done by (a) developing efficient numerical methods that describe spatially expanding, evolving populations, and (b) deriving laws of spatial population dynamics, including rates of fitness valley crossing and scaling laws for the mutant load for different mutant types. The evolutionary theory will be applied to data on cellular evolution in Rhabdomyosarcoma mouse xenografts, which are characterized by both spatial and hierarchical structure. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2023 · 2023-10

This Faculty Early Career Development (CAREER) grant will improve our understanding of the mechanistic origins of fatigue fracture in aged and diabetic fragile bones. This will be achieved by combining low-radiation images of bone damage with mechanical testing of bones and machine learning. This is important because fatigue (cyclic) fracture is a prevalent failure mechanism in nearly all engineered structures, but its relevance to the field of bone tissues has been neglected. These fatigue fractures are common in young athletes, especially in dancers. These fractures are also common in those who have bone fragility. For example, aged and diabetic bones have poor collagen quality and become fragile. Fractures are often thought to be the result of a single overload event, such as a fall. However, this may not explain the cause of all catastrophic fractures because it overlooks the role of fatigue from daily activities. This research project will develop novel dynamic imaging and machine learning for capturing the origins of bone failure mechanisms and associated risk factors. The results will ultimately be used to prevent fragility fractures. This research will provide a transferrable methodological framework for medical imaging, and foster the development of new fracture-resistant materials inspired by biological design principles. The research will be integrated into a long-term educational plan to attract the next generation of female engineers through dance class and other creative learning supports. It is of note that female engineering students in Utah, where this work will be done, are particularly underrepresented in comparison to the rest of the United States. The specific goal of the research is to advance the development of new bone fracture mechanics theory by using a novel synthesis of synchrotron radiation micro-computed tomography and specific machine learning algorithms to capture the 3D damage evolution during mechanical loading. Previous work has shown that this is typically not achievable by standard synchrotron micro-computed tomography imaging, which involves high radiation doses and causes deterioration of tissue’s mechanical properties. The research work will test the hypothesis that collagen cross-linking accumulation and other diabetic changes in bone quality play an important role in driving fragility fractures. The research tasks of this project include: (i) determine the (sole) effect of collagen cross-linking accumulation on fatigue and fracture resistance ; (ii) evaluate the contribution of collagen cross-linking accumulation in diabetic bone resistance compared with other bone quality factors; (iii) quantify the microscale failure mechanisms in deforming diabetic and crosslinking-rich bones during in situ fatigue and fracture tests; and (iv) evaluate whether cyclic loadings might drive a significant fraction of fractures in diabetic and crosslinking-rich bones. This project can reveal the origins of damage mechanisms in all types of collagenous tissues, and has the potential to lower the radiation level and improve image quality of medical scans. This new knowledge will establish the PI’s long-term career in bone fracture mechanics. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2023-09

Glaucoma is a leading cause of blindness worldwide and glia-driven neuroinflammation is a key element in the pathogenesis of glaucoma. Increasing evidence from clinical studies indicate that primary open-angle glaucoma is linked to single-nucleotide polymorphisms of toll-like receptor 4 (TLR4), mitochondrial cytochrome c oxidase subunit I of the oxidative phosphorylation (OXPHOS) complex-IV, ATP-binding cassette transporter A1 and Cholesterol-24S-hydroxylase, suggesting that TLR4-mediated neuroinflammation, cholesterol efflux and/or OXPHOS stress-mediated mitochondrial dysfunction play roles in glaucoma pathogenesis. ApoA-I binding protein (AIBP), encoded by the APOA1BP gene, is a secreted protein, which serves as a selective regulator of cellular cholesterol metabolism, targeting inflammatory cells via its binding to TLR4. Cholesterol depletion from inflammatory cells reduces lipid raft abundance and the membrane occupancy of receptors (such as TLR4) that mediate inflammatory signaling. Emerging evidence from our group showed that AIBP deficiency is associated with glia-driven inflammatory TLR4/interleukin-1β signaling axis and mitochondrial dysfunction in glaucomatous degeneration. In addition to protecting retinal ganglion cells (RGCs) against neuroinflammation, AIBP prevents RGC mitochondrial dysfunction in glaucomatous neurodegeneration. In preliminary studies, we demonstrated that AIBP expression is highly reduced in glaucomatous human and mouse RGCs and their axons, as well as Müller glia, and that amplification of retinal AIBP expression by adeno-associated virus delivery protects RGCs and preserves visual function in experimental glaucoma in vivo. In addition, treatment with recombinant AIBP protein promotes mitochondrial function in Müller glia against elevated pressure in vitro. Based on our previous and these findings, we propose to test the novel concept that AIBP controls retinal neuroinflammation and the RGC mitochondrial dysfunction, which lead to glaucomatous neurodegeneration, as well as to test the therapeutic potential of raising AIBP expression in the retina. The Specific Aims of this proposal are: (1) to define the mechanisms by which AIBP controls TLR4-lipid raft activation in inflammatory Müller glial cells; (2) to determine the protective mechanisms of AIBP amplification on mitochondrial network and bioenergetics in glaucomatous RGCs and Müller glial cells; and (3) to determine how therapeutic augmentation of AIBP expression impacts structural integrity and synapses linking RGCs and the central visual pathway. Our proposed studies will explore novel pathways which potentially link neuroinflammation regulation to elevated IOP-mediated mitochondrial function and cellular cholesterol metabolism. This work may also lead to the development of a new glaucoma therapy.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY/ABSTRACT As people with HIV (PWH) enter older adulthood, there is a growing public health need to preserve everyday functioning in aging PWH. PWH disproportionately experience adverse factors including neurocognitive impairment (NCI) and psychiatric (e.g., depression) and medical (e.g., diabetes) comorbidities relative to age- comparable peers without HIV. Together, these factors put older PWH at risk for everyday functioning decline. Despite this, there are few studies on the longer-term patterns and correlates of everyday functioning change in PWH, and there is no well-validated multivariable risk index informed by such longitudinal data. Therefore, the research aims of this F31 will delineate unique longitudinal trajectories of everyday functioning in PWH; and develop and initially validate a risk index of adverse and protective factors based on longitudinal modeling to identify PWH at risk for functional decline. This project will be conducted with support from an interdisciplinary mentorship team at the University of California, San Diego (UCSD) HIV Neurobehavioral Research Program (HNRP), a leading research center with experts in HIV and aging. The proposed F31 will leverage access to two archival longitudinal studies: CNS HIV Antiretroviral Therapy Effects Research (CHARTER; N = 704) and Multi-Dimensional Successful Aging Among HIV-Infected Adults (N = 106), that were conducted and/or coordinated at the HNRP. Accordingly, the specific aims are to: 1) identify unique everyday functioning trajectories in a development dataset (CHARTER); 2a) develop a prediction model using adverse predictors for functional decline in the development dataset; 2b) validate the model in the development (CHARTER) and validation (Successful Aging) datasets; and 3) determine if positive psychological factors add incremental value to predicting functional decline. The training plan proposes rigorous statistical training in developing advanced longitudinal predictive models of everyday functioning, combined with specific mentoring in the understanding and uses of biopsychosocial variables relevant to aging PWH as potential predictors. This F31 application is in line with the National Institute of Aging’s (NIA) mission to support and conduct biological, clinical, behavioral, and social research on aging; in addition to their mission to foster the development of research and clinician scientists in aging. It is also in line with an NIH Office of AIDS Research (OAR) priority for well-validated, multivariable indices that combine a range of biological to behavioral measures to predict which PWH are at high-risk for adverse outcomes. The opportunities afforded via this F31 mechanism will facilitate the applicant’s professional development toward becoming an independent academic neuropsychologist dedicated to promoting successful aging among older PWH.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT The North American overdose crisis remains at epidemic levels, with over 1 million lives lost over the past decade. This crisis is primarily driven by the emergence of high- potency opioids such as fentanyl, in unregulated (“street”) drug markets. However, the volatility of these markets has also led to the emergence of other even more potent opioids such as carfentanil and nitazene-class opioids, along with adulterants such as benzodiazepines. These emerging drug threats produce complex overdose presentations and difficulties in overdose reversal, all of which contribute to overdose mortality. Drug checking services, which provide individuals with analytic information regarding the presence of compounds in drugs of unknown composition, are increasingly employed in North America to prevent overdose mortality during the era of high-potency synthetic opioid contamination. However, current efforts to implement and expand access to drug checking services are hampered, primarily because current available technologies have logistical, technical, and cost-related barriers that impede their feasibility as point-of-care interventions. This is exacerbated by the need for ongoing assay development to ensure that drug checking technologies can continue to accurately detect and identify novel high-potency drug threats in North American drug markets. Meeting these needs is critical to advance the effectiveness of drug checking at the population level, particularly for drug checking service providers, individuals who use drugs, and medical examiners undertaking forensic investigations of overdose mortality. The aim of the current project is therefore to develop and validate a novel point-of-care technology, known as DoseCheck, for rapid non-targeted identification of emerging drug threats. Specifically, we will: 1) validate the DoseCheck system’s capacity to differentiate between and within classes of opioid, stimulant, depressant, and anesthetic compounds in non-targeted analyses of unregulated drugs; 2) undertake timed exercises to evaluate the capacity of our team to rapidly adapt the DoseCheck system to detect and differentiate a novel emerging drug threat; and 3) test the capacity of the DoseCheck system to identify and differentiate distinct opioid metabolites within human biomatrices. Achieving these aims will generate high impact and highly translational findings that will support the expansion of adaptive, analytically sophisticated, and low-cost point-of-care drug checking services and thereby contribute to a reduction in overdose mortality.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY This application is for an administrative supplement to DA058314, Development of practical screening tools to support targeted prevention of early, high-risk drinking substance use. The purpose of the supplement is to preserve, generalize, document, and disseminate a unique research material we have developed for the DA058314 project. Namely, we aim to create an open-source toolkit of bespoke metadata, code, and workflows that will allow end-users to quickly create and evaluate practical instruments for screening or prediction of any outcome of their choosing in the ABCD Study. Today, the breadth and complexity of the ABCD Study poses a major barrier to outside users pursuing the development of screeners or other prediction instruments. By lowering these barriers, the toolkit we develop will unlock the unprecedented potential of the ABCD Study for developing accurate, equitable approaches to risk estimation and prediction, in turn improving the ability of clinicians, policymakers, and scientists to allocate resources efficiently. We will disseminate the toolkit via a free R package, a website, peer-reviewed publications, and webinars. The administrative supplement is needed to support an additional staff member whose time will be devoted to these activities and complete this work in parallel to ongoing work on the parent award.

NIH Research Projects · FY 2024 · 2023-09

Project Summary One of the most prevalent consequences of infant deafness worldwide is delayed age of exposure to language which is known to lead to lower performance on language tasks both in the eventual first (Mayberry, 1993; Mayberry & Eichen, 1991) and second languages (Mayberry, 2007; Mayberry & Lock, 2003). The proposed studies investigate the development of argument ordering in three populations of deaf individuals who were exposed to three distinct sign languages: American Sign Language (200 years old), Vanuatu Sign Language (5 years old) and Fijian Sign Language (30 years old). Together, the three proposed studies examine the interplay of age of first exposure to language (Aim 1) and age of language community (Aim 2) on the development of argument ordering. In typical development, children with early language exposure to an established language produce the argument ordering of their environment in their early multi-word productions and rely on morphosyntactic argument marking in comprehension by the age of six years. In emerging sign languages, grammatical devices, including word order, develop over subsequent generations or cohorts as children not only acquire the language around them but create linguistic structure. The proposed studies use a picture description paradigm to elicit productive language from deaf participants who are signers of either an established language (ASL) or an emerging language (Vanuatu and Fiji). For analysis of which orders of arguments are prevalent in each population, stimuli of the production tasks are divided into event types based on transitivity and reversibility. These factors are salient in child language development and have been shown to elicit different argument ordering in emerging sign languages and homesign. Between subject analyses will compare the argument ordering of participants within each study as a function of their age of first exposure to language. Comparison across the three studies of the proposal will elucidate the effects of age of language community on the argument ordering used by deaf people in various settings. Together, the proposed studies will provide insight the creation and acquisition of language by deaf people around the world. In addition, this research project will enhance the applicant’s graduate school training, and greatly increase her chances to have a productive career as an independent researcher focusing on the effects of language deprivation and delay due to infant deafness.

NIH Research Projects · FY 2025 · 2023-09

Project Summary. Cancer deaths remain at an all-time high in the United States leaving an urgent clinical need to develop novel therapeutic strategies to help patients. The lack of effective treatments is in part due to underlying complexities in cancer that current scientific approaches are just beginning to uncover. Technological advances are rapidly changing the landscape of scientific discovery; for example, the combination of mathematical modeling in tandem with laboratory based validation leading to better combinational therapies to treat cancer. For this reason, I propose training in both with the F99/K00 Predoctoral to Postdoctoral Fellow Transition Award. For the F99 phase, the dissertation research, I will focus on laboratory based research skills to identify and propose a novel therapeutic to treat cancers. In a high level CRISPR screen targeting about 580 genes on the cell surface we found that Integrin Alpha V (ITGAV) is essential for the survival of solid tumors (colon, pancreatic, and breast cancer). To validate ITGAV as the most essential integrin we designed a second layer screen targeting all 26 integrins and found that ITGAV and Integrin Beta 5 (ITGB5) are the only essential integrins in solid tumors. Interestingly, integrins must for an obligate heterodimer between an alpha and a beta subunit of which ITGAV and ITGB5 are one of the known 24. As the more essential pair, ITGAV was probed with a high-density CRISPR tiling scan and we found a small pocket to be essential for ITGAV function and it was amendable to small molecule binding. A structure based analysis found a loop structure of the beta pair of ITGAV interacts with the discovered pocket, leading to our hypothesis that the pocket is essential for the heterodimer stability between ITGAV and its beta pair. Indeed, from a high-throughput screen of 500 small molecules we found one compound that appears to bind in our pocket and disrupt the heterodimer between ITGAV and ITGB5. Further validation of this potential will be the remaining work to be done for the dissertation research and upon completion, will fill an unmet clinical need since no there no FDA approved drugs targeting integrins approved for cancer indications. To further advance the potential to treat cancer I plan to use mathematical modeling approaches to identify novel therapeutic strategies by understanding the complexities of cancer signaling during the K00 phase, the proposed postdoctoral work. To study complex cancer signaling, in collaboration with Dr. Pirrotte, we generated kinase activity scores in cells where ITGAV was knocked out. With this data we can model the effects of signaling as it relates to measurable changes in the cancer cells. Specifically, we will study cell cycle control, which is inhibited with ITGAV loss. Additionally, we can model known inhibitors to common signaling cascades as novel combinational therapeutic strategies. To confirm our model, I will use laboratory based skill developed during the F99 phase. Overall with the training with the F99/K00 award I will gain skills to be able to build mathematical models to study cancer and validate those models with laboratory based skills. This will allow me to become and independent research and leading scientist in translational research.