Texas A&M University

NIH Research Projects · FY 2026 · 2020-09

Project Summary/Abstract Click chemistry has revolutionized modern synthesis, enabling diverse applications such as biomolecule labeling and polymer functionalization. The hallmark features of click reactions—modularity, broad applicability, exceptional chemoselectivity, and high yields with minimal purification—offer unparalleled opportunities for molecular design. However, conventional click linkers (e.g., triazoles) typically function as inert covalent bridges between molecules, such as a drug and a target-recognition warhead, without providing additional functionality or improving key properties, such as binding affinity. Their inherent stability makes these linkers unsuitable for selective chemical modification under mild conditions. Consequently, click reactions are not typically part of the medicinal chemist's toolkit for diversifying bioactive scaffolds through systematic functional-group variations, including ‘single-atom’ logic. We propose to shift this paradigm through the development of editable click linchpins that can be selectively converted into prevalent C–C or C–X bonds (X = heteroatom). Our strategy seeks to leverage the efficiency, practicality, and robustness of click chemistry to construct the bonds found in all pharmaceutical agents. The overarching theme of our ‘click and modify’ approach is to transform primary amines into 1,2- dialkyldiazenes and subsequently harness their unique photochemistry into a variety of catalytic deaminative processes. Primary amines represent one of the most abundant family of commercially available building blocks for synthesis and are ubiquitous across a diverse array of structurally complex biomolecules, including amino acids and peptides, biogenic neurotransmitters and signaling molecules, lipids, amino sugars, as well as alkaloid secondary metabolites. To streamline the access to 1,2-dialkyldiazenes from the large pool of primary amines, we developed an efficient and practical one-pot process Sulfur(VI)-Fluoride-Exchange (SuFEx) click chemistry coupled with the aza-Ramberg-Bäcklund reaction. The propensity of 1,2-dialkyldiazenes to undergo clean homolytic fragmentation under photocatalytic ambient conditions will be leveraged as a branching point for selective functionalizations via the controlled generation of alkyl radicals. We will first focus on strategies for forging C(sp3)–C(sp2) bonds through the deamination of a broad range of primary amines. A thorough understanding of the mechanism underpinning the proposed catalysis will enable the use of a variety of coupling partners and the optimization of enantioselective variants. Concurrently, strategies for C(sp3)–C(sp3) and C(sp3)– X couplings will be explored from the same alkyl radicals. Finally, the synthetic potential of this diverse transformation manifold will be demonstrated through the synthesis of macrocyclic or stapled peptides and construction of polymers for healthcare applications.

NIH Research Projects · FY 2025 · 2020-08

Project Summary/Abstract Anxiety is one of the most prevalent and costly problems facing mothers and their young children. Theoretical models about the etiology of anxiety risk, reflecting bidirectional associations between mothers and offspring, have gone largely without direct empirical testing. This has left a critical gap in knowledge regarding the nature of familial risk that will be necessary for a full understanding of the etiology of anxiety problems, one of the most prevalent, pervasive, and costly public health concerns in the present day. Two specific barriers to the successful prevention and treatment of anxiety problems include (1) an absence of empirically validated models that elucidate bidirectional influences between mothers and children, and (2) a lack of knolwedge of the neurobiological mechanisms that may serve as mediators for the bidirectional transmission of anxiety risk in mothers and offspring. Results from this project will contribute to the scientific knowledge base of anxiety risk in children and mothers across infancy and toddlerhood. This projects adopts a unique longitudinal multi-trait, multi-method design to test three biological systems as mediators of bidirectional effects of anxiety risk in mother-child dyads between child ages 1 and 3 years. Multiple aspects of negative valence systems are used to represent risk for anxiety in both children and mothers, and multiple biological arousal and regulatory systems are studied as mechanisms. Consistent with an RDoC framework, the project adopts a dimensional approach and utilizes both targeted and general sampling methods. The work proposed uncludes simultaneously testing maternal-based effects on child anxiety risk and child-based effects on maternal postpartum anxiety symptoms (Aim 1). Neural and neuroendocrine function in mothers and children will be tested as systems through which anxiety risk may be transmitted within the dyad (Aim 2). Children and mothers will be assessed via observation and surveys for levels of anxiety risk (fear, worry, anxious behaviors) and anxiety (anxiety symptoms) at each of three time points (child age 1, 2, and 3 years). This model will allow for the analysis of both concurrent and longitudinal associations between mother and child anxiety risk while accounting for individual stability in these systems. Aim 2 tests biological systems of neural (EEG, ERP) and neuroendocrine (cortisol) reactivity as mediators of transactional links between maternal and infant anxiety risk. Results will not only empirically test long-standing theories of child development, but will also inform the timing and framework for future family-based interventions aimed at preventing or ameliorating long-term anxiety problems in both mothers and young children, aligning with the National Institute of Mental Health’s mission to chart trajectories of mental illness and inform their prevention.

NIH Research Projects · FY 2026 · 2020-08

Project Summary The incorporation of nitrogenic functionality into organic small molecules has a profound effect on chemical structure, properties, and bioactivity. Current methods to install nitrogen rely on substrate pre-functionalization or elaboration of nitrogen-containing starting materials and confront synthetic limitations that prevent systematic amine derivatization. Efforts to develop nitrene transfer catalysis provide mechanisms to install nitrogen in place of C–H bonds and olefins, but also confront limitations: Namely, structural diversification at nitrogen, which is critical to modulating molecular function, are often incompatible with the nitrogen sources needed for nitrene transfer chemistry. The central hypothesis of this proposal is that a new build-and-couple synthetic paradigm will powerfully enable the synthesis, validation, and optimization of nitrogen-containing bioactive small molecules. Build-and-couple chemistry is inherently compatible with activity-based protein profiling for the identification and optimization of small molecule ligands for novel protein targets. This proposal specifically aims to develop reductive cross-electrophile coupling reactions that leverage the reductive lability of N-aminopyridinium salts for C–N bond construction. Extension to in situ amine activation ¾ via phenothiazine redox chemistry ¾ will unlock direct functionalization of the native amine functionality of bioactive scaffolds, complex molecules, and molecular therapeutics. We further seek to advance the synthetic chemistry of N-pyridinium aziridines as lynchpin intermediates for proteomics experiments. N-Pyridinium aziridines display atypical chemoselectivity towards the proteome, selectively functionalizing glutamate and aspartate sites. To unlock the potential of this atypical selectivity to develop small molecule ligands against “undruggable” protein targets, we advance a suite of novel N-functionalization methods. Finally, fragment coupling strategies, to introduce new pharmacophores in fully elaborated molecular scaffolds, are described. Together, the described program in build-and-couple synthetic chemistry introduces new disconnections, new molecular scaffolds, and new mechanisms of action for the discovery and optimization of nitrogen-containing amines.

NIH Research Projects · FY 2024 · 2020-07

Project summary Genome structure, at a fundamental level, can be described by the division of the genome into autosomes and sex chromosomes. Meiotic drive, segregation mechanisms, sexual antagonism, epistasis, benefits of higher or lower recombination, and drift have all been implicated in changes in chromosome number as well as the proportion of the genome contained within sex chromosomes. However, despite over a century of work, none of these factors can adequately explain the striking variation in genome organization across species. The long-term goals of our research program are: (1) to develop new and robust models to better explain the forces that lead to changes in the number of chromosomes and the proportion of the genome contained in sex chromosomes, and (2) to understand how these characteristics impact the evolution of other traits including common chromosomal disorders like Klinefelter syndrome and Turner syndrome. This will be achieved by implementing a three-pronged approach combining comparative, genomic, and theoretical methods to gain new insight into genome evolution. First, comparative phylogenetic methods will be applied to genomic and phenotypic data spanning long evolutionary time scales to estimate the rates of evolution of sex chromosomes and chromosome number and link variation in these rates with life-history or other traits. Over shorter time periods genetic and genomic studies are used within and among species to understand the nature of segregating variation in genome structure and genetic variation that is sexually antagonistic. Finally, these approaches are supplemented with theoretical work to test and develop hypotheses inspired by results or to aid in experimental design for genetic and genomic studies. Together, the results of this work will be an unprecedented understanding of the evolutionary forces that have shaped the large-scale structure of genome across the tree of life and continue to impact our genomes today

NIH Research Projects · FY 2026 · 2019-05

The vision for the Texas A&M Center for Environmental Health Research (TiCER) is to nucleate environmental health research and translational activities of investigators around the overarching theme “Innovative solutions for addressing exposure-stressor interactions”. This vision will be achieved by building on Texas A&M University’s ongoing investments in people and facilities and a history of state-wide outreach to community stakeholders. Existing investments through the Center provide infrastructure and an outstanding base of scientific expertise ready to catalyze innovative studies into environmental health solutions in communities, build multi-disciplinary collaborations among Center members to elucidate mechanistic links between environmental exposures and adverse health outcomes and ultimately translate data to action. The Center will continue recent successes in mentoring junior faculty, advancing career development and leadership opportunities, recruitment of additional established investigators into environmental health research, and fostering a multi-disciplinary, team-oriented intellectual environment among Center members representing 11 colleges at Texas A&M. The Center’s vision is guided by two research themes spanning fundamental and applied research: 1) Stressors to Responses and 2) Environment and Metabolism, which will be coordinated through a highly integrated set of Facility Cores. The Translational Research Support Core (TRSC) will support bi-directional translational workspaces including development and toxicology models and exposure science resources to ensure Center member access to unparalleled instrumentation and cores. Together with the Data Science Core, these resources will enhance the capacity, breadth, collaborative nature, and impact of environmental health research. The Administrative Core and Pilot Project Program will facilitate TiCER’s function by ensuring continuation of the highest levels of institutional support, fostering career development, and promoting multi-disciplinary team science that generates knowledge to action. The Community Engagement Core will be a critical vehicle for implementation of a multi-prong strategy of the Center by serving as a bi-directional portal to connect Center members and stakeholders. Overall, the Center will expand the established investigator base and expertise in cross-cutting environmental health science that can be deployed to increase the impact of environmental health research in Texas and beyond.

NIH Research Projects · FY 2025 · 2019-04

PROJECT SUMMARY Genomic structural variants (SV) involving deletions, duplications, insertions, inversions, and translocations of sequences are an abundant source of genetic variation. SVs have been linked to Mendelian diseases, as well as complex heritable diseases like schizophrenia, and cancer. However, recent comparisons of extremely contiguous genome assemblies of humans and model organism Drosophila melanogaster have revealed that common genotyping strategies relying on high throughput short reads miss 40-80% of SVs, including those affecting phenotypes. Thus, contribution of SVs towards diseases and phenotypic variation remain grossly underestimated. To accurately measure the contribution of SVs towards deleterious genetic variation and trait variation, we propose to create a comprehensive map of genomewide SVs via comparison of extremely contiguous genome assemblies. However, contiguous de novo assembly of human genomes with high coverage (>50X) noisy long reads remains prohibitively expensive. So I propose to analyze SVs in the 25-fold smaller genome of model organism D. melanogaster, which has contributed substantially to our understanding of the genetics of complex human diseases. The proposed research aims to study fitness effects of polymorphic SVs based on de novo genome assemblies of 50 genetically diverse D. melanogaster strains that are as complete and contiguous as the current D. melanogaster reference genome – arguably the best metazoan genome assembly (Aim 1). I propose to use this comprehensive set of variants to infer the distribution of fitness effects of the SVs and to estimate the proportion of adaptive SVs, both of which are reliable proxies for the evolutionary and functional significance of SVs (Aim 1). Aim 1 will involve training in theory and cutting edge methods in molecular population genetics. Next, the proposed project will develop an experimental approach to determine the fitness effects of variants for which an organismal phenotype is unknown. As part of this, the proposed project will develop genome editing resources that will facilitate rapid transformation of one of our sequenced strains with SVs, so that fitness effects of candidate SVs from trait mapping studies can be examined (Aim 2). Training in Aim 2 includes development of CRISPR-Cas9 toolkit in a common genetic background to investigate the functional effects of SVs. Finally, using the toolkit developed in Aim 2, we propose to conduct high throughput fitness assays to evaluate the selective effects of SVs under specific selection conditions (Aim 3). The training portion of the proposed research will complement the applicant’s previous experience and position him for a successful research career. University of California Irvine and the Emerson and Long labs together have the resources and expertise to ensure the successful completion of the training phase of the grant.

NIH Research Projects · FY 2026 · 2018-05

Summary (Paul Alan Lindahl, PI) This MIRA renewal focuses on the cell biology of iron and to a more limited extent on copper. Transition metals have exceptional properties that render them indispensable for life, but they are also dangerous to the cell, such that trafficking must be tightly regulated. The PI is developing innovative and powerful approaches to fill huge gaps in understanding transition metal ion trafficking and regulation, especially in mitochondria which are iron and copper “traffic hubs”, and in the cytosolic Labile Fe Pool (LFeP) which accepts nutrient iron and distributes them to ~ 100 client apo-proteins in yeast cells. The chemical identity of the LFeP remains unestablished due to its inherent lability. To investigate such pools, the PI and his coworkers employ a novel custom liquid chromatography system in a refrigerated anaerobic glove box interfaced to an inductively-coupled plasma mass spectrometer (ICP-MS). Mössbauer (MB) spectroscopy is used to characterize the iron content of 57Fe-enriched cells, organelles, mouse organs, and blood plasma. Differential equations-based mathematical models are designed and developed to help understand the kinetics and mechanism of Fe trafficking in growing yeast cells. Few groups use any one of these innovative tools and no other lab worldwide uses all of them. This affords the PI a unique opportunity to solve critical problems in this field. In the past 5 years, with NIH MIRA support, the PI has published 23 peer-reviewed papers. Moving forward, the Lindahl lab will continue to investigate labile metal pools in biological systems using these approaches, coupled with electrospray ionization mass spectrometry (ESI-MS). Innovative chromatographic methods will be developed to minimize the lability of metal complexes. Most studies will use yeast cells, but labile metal pools in mammalian cells will also be investigated. How the LFeP changes with different genetic strains, metabolic conditions, and nutrient levels will be assessed. The LFeP in intact yeast cells will be detected and characterized by MB spectroscopy. The Fe/S species (known as X-S) that is exported from mitochondria into the cytosol will be identified. The LFeP in mitochondria will be reinvestigated using improved methods. Sophisticated and realistic mathematical models will be developed to simulate the kinetics of Fe trafficking and regulation. Whether non-transferrin-bound iron (NTBI), found in iron- overload diseases, is a high-molecular-mass FeIII aggregate or an FeIII citrate complex will be determined. Copper homeostasis and the mechanism of copper trafficking from cytosol to mitochondria will be probed, focusing on the role of metallothionein Cup1 in homeostasis, and on Cox17 and small nonproteinaceous CuLMM complexes as candidate trafficking species. Low-molecular mass CuLMM complex(es) will be isolated and identified by ESI-MS.

NIH Research Projects · FY 2026 · 2018-05

Summary The circadian clock, critical to human health and drug metabolism, regulates rhythmic protein production and thus cell function and metabolism. Many proteins whose levels show robust circadian rhythms are produced from mRNAs that are not rhythmic. Using the model eukaryote Neurospora crassa, we found that up to half of this circadian regulation of protein levels is through clock control of the activities of a conserved regulator of translation initiation (eIF2α), and the protein composition of translating ribosomes. We also made the surprising observation that the circadian clock controls the probability that ribosomes will read through the normal stop codon to produce proteins with carboxy-terminal extensions and potentially new functions. In addition, we found that the clock regulates the levels of tRNA synthetases that charge tRNAs with the appropriate amino acids for translation, and thus are critical for accurate protein synthesis. Over the next 5 years, we will capitalize on these findings to test the exciting hypothesis that the circadian clock controls daily changes in translation fidelity and thus protein diversity beyond what is encoded for in the genome. We will determine if clock control of ribosome composition is necessary, and which specific ribosomal proteins are required, for rhythmic stop codon readthrough. In addition, we will test if circadian clock control of binding of the co-chaperone Zuotin to ribosomes regulates daily rhythms in protein folding. We will determine the impact of circadian rhythms in methionyl-tRNA synthetase (MetRS) levels, and rhythms in the activities of kinases that phosphorylate MetRS, on three different MetRS regulatory pathways. These include translation initiation through charging of the initiator methionyl tRNA, translation elongation through charging of elongator methionyl tRNA, and misincorporation of methionine during protein synthesis through the mischarging of non-cognate tRNA. This work will significantly impact our understanding of both how a cell is different at different times of the day, and how the proteome can be more diverse than what one would predict from the genome sequence.

NIH Research Projects · FY 2025 · 2017-09

Project Summary/Abstract The increasing appreciation of RNA’s structure-function relationships has led to a demand for new technologies that enable targeting of specific RNA structures. However, discovery of molecules that are capable of binding RNA structures with high affinity and selectivity has proven challenging using current approaches, resulting in a technological gap that precludes the development of new research tools to study RNA function and therapeutics to treat RNA-mediated diseases. Thus, development of new technologies that enable structure- specific targeting of RNA remains an important challenge in many fields. The central vision of my research program is to address the deficit of structure-specific RNA-binding reagents using a radically different type of nucleic acid affinity reagent: L-aptamers. L-Aptamers are unique because they are comprised of L-(deoxy)ribose-based nucleic acids (L-DNA and L-RNA), which are mirror images (enantiomers) of natural D-nucleotides. Because oligonucleotides of opposite stereochemistry (D versus L) are incapable of forming contiguous Watson-Crick base pairs with each other, we are able to evolve L-aptamers that adaptively bind structured D-RNA targets through tertiary interactions (shape) rather than primary sequence. This unique “cross-chiral” mode of recognition occurs with high affinity and selectivity, and these interactions can modulate the function of RNA targets through several modes of action. These properties, coupled with the intrinsic nuclease resistance of L-oligonucleotides, provide L-aptamer technology a broad range of opportunities in biomedical research and disease intervention. During the next five years, my research group aims to further develop L-aptamer technology to realize its promise as a practical research and therapeutic tool. We aim to improve the RNA-binding properties of L- aptamers using new in vitro selection strategies and to improve our understanding of cross-chiral recognition by providing the first three-dimensional structure of an L-aptamer-RNA heterochiral complex. Building on our prior work, we will continue to develop L-aptamers as inhibitors of oncogenic microRNAs, representing a promising therapeutic strategy for related cancers. However, we will also pursue several novel applications of L-aptamer technology, including RNA-targeted small molecule drug discovery and intracellular RNA imaging, thereby substantially broadening the impact of this work. Finally, we aim to comprehensively characterize the behavior of L-oligonucleotides in living cells — how they interact with these environments and the potential consequences — the results of which will have a broad impact on the development of all future L-oligonucleotide-based biotechnologies, including L-aptamers.

NIH Research Projects · FY 2026 · 2017-08

Daily rhythms in animal behavior, physiology and metabolism are driven by cell-autonomous circadian clocks that are synchronized by environmental cycles but maintain ~24h rhythms even in their absence. These clocks keep circadian time and control overt rhythms via transcriptional feedback loops (TFLs). Because clock dysfunction negatively impacts human health, characterizing mechanisms that drive TFLs is of critical importance. The goal of this proposal is to understand how feedback repression, a key event controlling rhythmic transcription, is achieved using two complementary model systems; the monarch butterfly and the fruit fly Drosophila melanogaster. Animals possess two TFL paradigms with orthologous components: A Drosophila-like (dl) paradigm in which CLOCK (CLK) activates and PERIOD (PER) represses transcription, and a mammal-like paradigm (ml) in which CLK-BMAL1 activates and PER-CRYPTOCHROME (PER-CRY) complexes repress transcription. Monarch butterflies have an ml clock, but unlike mammals, monarchs carry single copies of clock activator and repressor genes, thus making it an attractive model to dissect clock mechanisms relevant to mammals. Common features of dl and ml clocks are that PER complexes containing CASEIN KINASE 1 (CK1) initiate transcriptional repression `on-DNA' by binding CLK complexes on E-box elements, followed by CK1-dependent PER and CLK phosphorylation, removal of PER-CLK complexes from E-boxes to initiate `off-DNA' repression, and ultimately PER degradation. How PER orchestrates transcriptional repression is poorly understood. We recently identified a region in CLK that acts as a conserved molecular hub to coordinate transcription activation and repression. The TRITHORAX (TRX) histone methyltransferase, which activates transcription by binding this hub, is also essential for repressing transcription by permitting CLK-PER binding. TRX mediates repression by directly or indirectly methylating the chaperonin HSP68, which is required for CLK-PER binding and repression. We also discovered that CLOCK-Interacting Protein Circadian (CIPC) also binds the CLK hub to repress transcription across animals. CIPC and TRX binding to the CLK hub suggests that CIPC inhibits transcription by displacing TRX, altering TRX substrate specificity to permit HSP68 R45 methylation, promoting PER-CLK binding, removing CLK-CYC from DNA and/or promoting co-repressor binding. These hypothetical CIPC functions will be tested in Aim 1. Our discovery that TRX methylation of HSP68 is required for PER-CLK binding and repression suggests that HSP68 acts in concert with progressive phosphorylation of unstructured PER and CLK regions to efficiently drive sequential structural changes that control DNA binding and protein interactions needed to maintain a ~24h circadian cycle. This hypothesis will be tested in Aim 2. Successful completion of these aims will provide mechanistic insight into how circadian repression determines the phase, period and amplitude of transcriptional rhythms. Ultimately, such knowledge may be broadly applied for diagnosis and treatment of diseases and ailments associated with clock dysfunction.

NIH Research Projects · FY 2025 · 2016-07

PROJECT DESCRIPTION Regulatory Science in Environmental Health and Toxicology This proposal is to continue the T32 program in “Regulatory Science in Environmental Health and Toxicology” at Texas A&M University. Funds are requested to support eight pre-doctoral (Ph.D. candidates) and two post- doctoral trainees in the existing highly integrated degree-granting Interdisciplinary Faculty of Toxicology program. Our goal remains to prepare trainees to function as independent researchers and/or practitioners in a multidisciplinary setting, by providing training in mechanistic research and risk assessment with a focus on scientifically sound, risk-based regulatory evaluations of the effects of drugs and other chemicals on human health and the environment. To achieve this goal, didactic and research experiences are offered by a team of 20 outstanding investigators who specialize in mechanistic toxicology, community engagement, exposure assessment/environmental chemistry, public policy, epidemiology, biomedical engineering, and data science and modeling. Recruitment is conducted through traditional external advertisement and professional societies, as well as from a number of existing Texas A&M programs that offer research experience for undergraduates, and public health and toxicology masters-level traineeship. Pre-doctoral trainees undertake two laboratory rotations in their first year in the program and follow a structured core academic curriculum that includes basic and advanced toxicology, histopathology, pharmacology, biostatistics and research ethics, combined with courses in risk assessment and exposure assessment. In the second year, additional specialized training is offered through elective courses that further prepare trainees for careers in research and/or public health practice. Distinctive features of the program are (i) a strongly encouraged hands-on summer externship through a broad and diverse network of state and federal governmental regulatory agencies, companis and non- governmental organizations; and (ii) a series of special programs in the form of boot camps and special workshops on a wide range of trainee-selected topics (scientific writing, presentation, interview skills, disaster research and data science). Following the first two years, trainee support for both pre- and post-doctoral fellows shifts to their mentor’s or independent funding. All mentors have strong records of competitive support from Federal, State and other sources and this group of mentors is exceptionally well balanced with respect to relevant scientific expertise, sex and academic career level. Graduates from the program are highly successful in academia, and sought-after by employers in the industry, governmental agencies and other professional settings. Our trainees improve public health protection through innovative and rigorous mechanistic research and risk assessment practice in support of rigorous scientific evidence-based regulatory decision-making.