Purdue University

NIH Research Projects · FY 2025 · 2016-08

Inflammation presents as swelling, redness, heat, and lost-of-function and is essential for the restoration of tissue homeostasis after injury and infection. Neutrophils are the major effector cells of acute inflammation that combat infection, promote wound healing and resolution of inflammation, while contributing to collateral tissue injury. In addition, neutrophils are exploited as vehicles that cross tissue barriers to deliver cargos to inflammation sites. A better understanding of the neutrophil-intrinsic mechanisms that regulate neutrophil migration will have broad translational importance in the prevention and treatment of a wide range of inflammation-related diseases. The challenges associated with studying neutrophils are a limited set of genetic tools and the plasticity of the cells in vivo. To address these challenges, the PI uses zebrafish, a genetically tractable vertebrate model with a well-conserved innate immune system. Findings on neutrophil intrinsic genes that regulate neutrophil migration generated in the zebrafish model are then validated in primary human or murine neutrophils. MicroRNAs are small RNA molecules of 22-24 nt that regulate homeostasis in health and disease. MicroRNA “mimics” and “inhibitors” are emerging as next-generation therapeutics because of their ability to modulate a network of genes. In addition, microRNAs are being used as tools to discover novel regulators of biological processes. A critical gap remains understanding how microRNAs regulate neutrophil function: despite the prominent microRNA profiling studies in neutrophils and in various diseases, microRNA functional studies are scarce. The PI’s lab has been at the forefront of addressing this unmet need by characterizing microRNAs and their targets in neutrophil migration. Building on their recent progress, the first project is to continue charactering microRNAs in regulating neutrophil migration with two sub aims: (1.1) identify microRNA targets as novel regulators of neutrophil migration and inflammation, and (1.2) characterize how RORα regulates neutrophil migration. A separate project is to characterize mechanisms delineating the role of mitochondria in neutrophil migration. Mitochondria fission promotes migration in many cell types, including lymphocytes, presumably by increasing mitochondria localization and ATP production at sites of high energy demand. On contrary, neutrophils possess a highly fused mitochondrial network and primarily use glycolysis for ATP generation, suggesting additional roles of mitochondria outside the realm of ATP. Specifically, the PI seeks to (2.1) characterize how MFN2 regulates neutrophil migration. The hypothesis is that MFN2-mediated mitochondrial-ER contact regulates Rac activation and neutrophil adhesion and migration. The PI will continue to (2.2) identify additional mitochondrial related genes as novel regulators of neutrophil migration and inflammation. An increased understanding of neutrophil migration and inflammation will open multiple fronts in cell biology and immunology. Additionally, as a result of this work, previously underexplored therapeutic possibilities to treat inflammatory diseases will come to light.

NIH Research Projects · FY 2026 · 2016-08

Project Summary/Abstract Excited-State Catalysis in Organic Synthesis Advancements in healthcare, agriculture, materials science, and sustainable energy rely on the efficient synthesis of structurally diverse, functional molecules. While ground-state catalysis has been highly successful in enabling numerous bond-forming and bond-breaking transformations, often with impressive selectivity under mild and sustainable conditions, certain transformations remain challenging due to inherent energetic and mechanistic limitations. To address these gaps, this proposal seeks to complement and expand existing catalytic strategies by leveraging visible-light-induced excited-state catalysis, a powerful approach that activates catalytic species through photoexcitation, enabling access to novel reaction pathways and reactivity landscapes that are difficult to achieve with ground-state methods. This research will focus on developing innovative synthetic methodologies that enable rapid, selective molecular transformations under mild conditions through three integrated research programs: (1) developing novel excited-state catalytic platforms for site-selective modification of carbohydrates, providing streamlined access to new derivatives with potential applications in medicine, imaging, and catalysis; (2) combining excited-state catalysis with 1,2-radical migration (RaM) to achieve 1,3-di- and 1,3- hydrofunctionalization of allyl carboxylates, offering new retrosynthetic disconnections and access to molecular scaffolds useful for drug discovery and materials science; and (3) establishing valence tautomerism (VT) as a general strategy for enantioselective cross-nucleophile coupling (CNC), enabling the construction of challenging quaternary carbon centers. Collectively, these programs aim to facilitate the rapid and sustainable synthesis of value-added compounds from simple feedstocks, unlock new reactivity pathways beyond ground-state catalysis, and advance synthetic transformations crucial for drug development, biocompatible materials, and molecular imaging. Supported by robust preliminary data, multidisciplinary collaborations, and access to state-of-the-art facilities at Purdue University, this research will expand the synthetic toolbox and drive innovation in organic chemistry, with significant implications for biomedical and material sciences.

NIH Research Projects · FY 2025 · 2016-08

Far-field fluorescence microscopy is a powerful tool in biological research due to its live cell compatibility and molecular specificity. A major hurdle over the last ~100 years has been the limited resolution due to the diffraction of light. Modern super-resolution microscopy methods such as single-molecule localization microscopy (SMLM) overcame this fundamental barrier and improved the resolution of fluorescence microscopy ten-fold by stochastically switching single dyes on and off such that their emission events are separated in time. This allows their center positions to be localized with high precision in space, leading to a reconstructed super-resolved image with a resolution down to ~25 nm. However, current developments and applications of SMLM focus on fixed cells in thin samples and cellular structures that lie close to the coverslip surface. Indeed, the profound impact of SMLM on biomedical studies has yet to fully unfold due to the following limitations: (1) live-cell SMLM is slow and difficult to achieve ultrahigh resolution due to the small photon budget, the insufficient information carried per photon, and the required high excitation power; (2) SMLM through large tissue depths remains difficult, due to the rapidly deteriorating resolution and image fidelity in tissue specimens caused by aberration and fluorescence background; and, (3) molecular resolution (1-5 nm) is yet achievable in whole cells and tissues at low photon flux conditions. Overcoming these hurdles will help reveal the structure, function and dynamics for cellular constituents at the molecular resolution in living specimens, and the reconstruction of nanoscale maps of multiple protein species within a large tissue volume. These capacities will drastically expand the impact of SMLM applications. Our long-term goal is to develop novel optical imaging systems that achieve significant advances in defining the structure and function of cellular constituents in live cells and tissues with molecular resolution. In the next five years, we will focus on two research directions: (1) We will develop novel single molecule super-resolution imaging technologies and a phase-encoded localization method to enable molecular-resolution 3D imaging in live cells under low photon flux conditions. The innovations will enable us to capture 3D dynamics with 1-5 nm resolution and construct time-evolved structural models of macromolecular assemblies in live cells. (2) We will develop novel instruments and analytical methods to allow ultra-high resolution, multiplexed mapping of fluorescently labeled targets in large tissue volumes. We will apply these developments to reveal the molecular organization and functions of networks of actin filaments and myosins during the formation and constriction of the cytokinetic contractile ring in live fission yeast. Also, we will determine the precise subcellular localization of molecular motors like dynein with respect to both microtubule and actin in neuronal growth cones. We will also explore the correlation between nanoscale topology of chromatin loci with defined epigenetic content and cell lineage and changes in gene expression profile.

NIH Research Projects · FY 2025 · 2014-06

PROJECT SUMMARY Targeting MYC promoter G-quadruplex for MYC inhibition by Indenoisoquinolines G-quadruplex (G4) DNA is a globular DNA secondary structure and considered as a new class of molecular targets for anticancer drugs. MYC, one of the most commonly deregulated genes in human cancers, has a DNA G4 motif in its promoter that functions as a transcriptional silencer. Compounds that bind to and stabilize the G-quadruplex formed in the MYC promoter have been shown to significantly lower MYC levels in cancer cells. Thus, the MYC promoter G-quadruplex (MycG4) represents a novel target for MYC inhibition by small molecules. However, little is known about how MycG4 is regulated by proteins and development of MycG4- targeting drugs has been focused solely on G4 DNA. Whereas drug-DNA interactions may be insufficient for MYC inhibition, the effective mechanism of drug action could involve protein-DNA interactions, which is analogous to topoisomerase inhibitors. Very recently, we have discovered that indenoisoquinolines, a clinically tested scaffold with excellent drug-like properties, are strong MycG4 binders and potent MYC inhibitors. We have also discovered that the DDX5 helicase actively unfolds MycG4 and is critically involved in MYC gene transcriptional activation. These results provide new and critical insights to effectively downregulate MYC transcription by targeting MycG4 and its interactions with DDX5. Our central hypothesis is that indenoisoquinolines effectively suppress MYC transcription by binding to the MYC promoter G-quadruplex and disrupting DDX5-MycG4 interactions. The overall objective is to determine the molecular mechanism of effective MYC inhibition by indenoisoquinolines, establish the structure–activity relationships (SAR), and discover lead indenoisoquinolines for preclinical testing. The long-term research goal is to develop potent indenoisoquinoline MYC inhibitors as new anticancer drugs. The specific aims are: 1) Structural characterization of the MycG4-indenoisoquinoline complexes. 2) Establishing a compound library to determine indenoisoquinolines that bind MycG4 and inhibit MYC. 3) Determining the effect of MycG4-interactive indenoisoquinolines on DDX5 unfolding of the MYC promoter G4 and how this correlates with MYC suppression. 4) Designing and synthesizing optimized indenoisoquinolines for MYC suppression using structure-based rational approach; establishing SAR for MycG4-binding and inhibition of DDX5 unfolding. The expected outcome of this work is a determination of the SAR of indenoisoquinolines for MycG4-targeting, demonstration of the effective MYC suppression by inhibiting DDX5-MycG4 interaction, and discovery of lead compounds for future preclinical testing. The results will have an important positive impact because they lay the groundwork to develop new indenoisoquinoline anticancer drugs with MYC-targeted activity.

NIH Research Projects · FY 2026 · 2011-11

The present proposal addresses a critical need to recruit and retain a strong and talented pool of scientists, by providing direct travel support to trainees to permit them to actively participate in the annual meetings of the International Society for Developmental Psychobiology (ISDP), a well-established, yet exciting and vital, scientific society devoted to a broad range of scientific questions that cross many levels of analysis. The mission of ISDP is to promote and encourage research on the development of behavior in all organisms. The annual meetings feature invited speakers, symposia, oral talks and posters that span developmental questions across species including humans, with special attention to the effects of biological factors operating at any level of organization. Funds from this grant have provided support for pre- and postdoctoral trainees to travel to these meetings. The present proposal requests 5 years’ continuation of travel support from NIH to continue supporting our ability to bring the brightest students and postdoctoral fellows to this meeting where they will be able to interact with others examining critical questions related to normal and abnormal development using scientific paradigms ranging from the molecular to the clinical. Providing multi-year support encourages a culture of active and continued participation at the ISDP meetings among graduate students and postdoctoral trainees, prolonging the impact well beyond the period of support requested.

NIH Research Projects · FY 2025 · 2011-04

RNA helicases are a class of enzymes that modulate RNA structure in living cells, functioning in every aspect of RNA biology from transcription to decay. However, the precise biological function of the vast majority of the ~40 eukaryotic RNA helicases is largely unknown. In the previous funding cycle, we provided one of the first identifications of in vivo enzymatic helicase targets for a DEAD-box helicase to date. Moreover, we uncovered a novel role for RNA structure remodeling in transcription termination of RNA polymerase II in S. cerevisiae. This activity is regulated in response to environmental cues to control the expression of metabolic genes, a role that we found is conserved in human cells with the mammalian DEAD-box helicase DDX5. Strikingly, OBP2- dependent non-coding transcripts termed long non-coding RNAs (lncRNAs) form RNA-DNA hybrid structures or R-loops upon inactivation of Dbp2 that function in gene regulation. However, the mechanism(s) linking these multiple observations remains unknown. Filling this gap is of key importance because misregulation of numerous RNA helicases, including DDX5, results in disease states such as neurological disorders and cancer. Major remaining questions are: 1. How does Dbp2-dependent RNA structure impact termination? 2. What is the relationship between R-loop suppression and Dbp2? 3. Does mammalian Dbp2, termed DDX5, function in termination regulation through RNA remodeling? Our central hypothesis is that Dbp2 and DDX5 are members of a novel class of epigenetic regulators that unwind RNA structures in nascent RNAs to control transcription termination and R-loop formation in response to cellular energy status. We propose to test this hypothesis with three, focused Specific Aims, which integrate newly established and innovative strategies with proven experimental techniques. In Aim 1, we will define how RNA structure impacts transcriptional termination. In Aim 2, we will determine the mechanistic relationship between Dbp2 and R-loop suppression. In Aim 3, we will identify the enzymatic targets of DDX5 in human cells and connection to transcription termination. This research is relevant to multiple aspects of RNA biology, gene regulation, and human disease.

NIH Research Projects · FY 2025 · 2009-07

Project Summary Despite recent technological advances, people still suffer from communication difficulties that impact their professional, social, and family lives, as well as their mental health. People with sensorineural hearing loss (SNHL) struggle with understanding speech, particularly in noisy situations. In fact, people with similar degrees of clinically defined hearing loss can have a wide range of speech-recognition abilities, likely due to differences in underlying suprathreshold deficits that are hidden from current audiological assessment. Although a listener’s sensitivity to simultaneously spectrally and temporally modulated (STM) sounds is known to be predictive of speech-in-noise performance in individual listeners, the underlying mechanisms of this predictive power remain a topic of active debate. Physiological evidence from our lab and others demonstrate that several forms of SNHL (e.g., OHC and/or IHC dysfunction) affect within and across-channel modulation coding of signals in different ways. For example, distorted tonotopy due to OHC dysfunction can affect the perceptually relevant within- channel signal-to-noise ratio in the modulation domain, as well as across-channel temporal coherence of modulations that are useful for source segregation. Despite these clear and varied implications for modulation coding of signals, these effects are surprisingly understudied with respect to signal-in-noise coding, which is the focus of the proposed work. We use a cross-species experimental design to collect anatomical, single-unit AN-fiber, evoked-response, and diagnostic data from several pre-clinical chinchilla models of SNHL, as well as evoked-response, diagnostic, psychophysical, and speech-in-noise data from human listeners spanning a range of age and hearing status. Aim 1 is to characterize SNHL effects on within-channel modulation masking, where the data collected will test the hypothesis that OHC and IHC dysfunction each degrade the perceptually relevant neural modulation signal-to-noise ratio, but in distinct ways. Aim 2 is to characterize SNHL effects on across-channel temporal coherence cues, where the data collected will test the hypothesis that distorted tonotopy is prevalent in both animals and human listeners and has a perceptually relevant effect on peripheral across-channel temporal coherence. Aim 3 is to characterize SNHL effects on STM sensitivity, where our cross- species data will test the hypothesis that the predictive power of STM stimuli for speech-in-noise perception arises largely from distorted tonotopy and the effects of SNHL on temporal modulation coding, rather than from broadened tonotopic tuning or degraded temporal precision. Data will be harmonized in an open-source data- science framework to facilitate future causal modeling by us and others. Our unique ability to quantitatively synergize cross-species data within a rigorous perceptually relevant framework will allow us to test our general hypothesis that SNHL has several distinct peripheral effects on modulation cues for signals in noise, which contribute to individual differences in speech perception in noise. Long-term, this work will help to personalize audiology by providing knowledge to stratify the clinical SNHL category in a framework of real-world significance.

NIH Research Projects · FY 2026 · 2005-07

PROJECT SUMMARY The ability of both low and highly pathogenic avian influenza (HPAI) viruses of H5, H7, and H9 subtypes to repeatedly infect humans reveals their zoonotic nature and pandemic potential. Besides, the seasonal influenza viruses (H1N1, H3N2 & influenza B) continue to evolve and pose significant public health threats worldwide. While candidate vaccine viruses can be made for individual influenza strains, it is impractical to prepare significant vaccine stocks for each of the potentially pandemic viruses. The significance of developing a universal influenza vaccine is of utmost importance for developing a better strategy for combatting seasonal as well as potential pandemic influenza viruses. We have developed a novel replication-defective bovine adenovirus (Ad) type 3 (BAd3)-based vaccine platform, which is better than the currently available Ad vector systems for providing heterologous influenza protection with dose sparing and is not impacted by the pre-existing human Ad vector immunity. Recently, we have revealed that the BAd vaccine platform induces significantly higher expression levels of the immunogen and innate and adaptive immunity-related factors compared to that of human Ad vectors in mice. We have also identified a 22 amino acid residues Autophagy-Inducing Peptide (AIP) C5 (AIP-C5) from the CFP10 protein of M. tuberculosis that enhances robust T cell immune responses in mice to NP of H7N9 influenza virus when delivered through an Ad vector. It conferred complete protection (from disease, death, or lung viral titers) against H1N1, H3N2, H5N2, H7N9, and H9N2 influenza viruses. Immunization of mice with an Ad vector expressing H5N1 M2e-HA2 [the extracellular domain of matrix 2 linked to the stem portion (HA2) of hemagglutinin (HA) with the HA signal peptide and the GCN4 leucine zipper trimerization domain] led to a significant reduction in lung viral titers following challenge with an H5N1 virus. This proposal is based on the hypothesis that a combination of heterosubtypic cell-mediated immune (CMI) responses against NP and the cross-reactive (not necessarily cross-neutralizing) humoral immune responses against NP or other conserved domains (M2e-HA2), when expressed with AIP-C5 and delivered through the BAd vaccine platform, will provide broad protection against potential pandemic H5, H7, or H9 avian influenza viruses as well as seasonal H1, H3, and influenza B viruses. The aims of this proposal are: i) To investigate immunogenicity and protective efficacy of novel antigen design and vaccine delivery platform in a mouse model for developing universal influenza vaccines (Aim 1); ii) To ascertain immunogenicity and protective efficacy of two selected universal influenza vaccine formulations in ferrets (Aim 2); and iii) To monitor virus transmission from the vaccinated to non-vaccinated animals, the quality of memory B and T cell responses, the durability of protective and vector immunity, and potential vaccine-associated enhancement of respiratory disease (Aim 3), utilizing the state-of-the-art technologies.

NIH Research Projects · FY 2026 · 2001-05

PROJECT SUMMARY Our understanding of how chronic Mn may trigger or promote central nervous system (CNS) morbidities remains fragmentary. Here, we seek to continue our studies into the mechanisms of Mn neurotoxicity by focusing on chronic exposures. Acute Mn cellular neurotoxicity occurs by alterations in cell signaling pathways that normally rely on Mn for their function, e.g., insulin-like growth factor (IGF)/insulin metabolic signaling pathway (IIS), and the highly interconnected mTOR (mTORC1 and mTORC2), AKT and ATM/p53 metabolic signaling systems. Existing research strongly supports a mechanism of Mn neurotoxicity related to the fact that Mn-dependent enzymes are situated at key regulatory nodes in these metabolic signaling pathways. New data support role for two other signaling systems linked to healthy aging in chronic Mn neurotoxicity, the eIF2 and Sirtuin (SIRT) signaling pathways. It is noteworthy that real-life Mn exposures in the human population occur over an extended period, months to years, involving lower extracellular or intracellular levels of Mn not associated with cell death in acute neurotoxicity studies. Mechanistic details underlying the biological changes that occur under chronic Mn intoxication remain elusive and thus warrant further investigation. Moreover, it is highly likely that persistent Mn effects are in a complex interplay with genetics, sex and age. Therefore, we seek to test the overarching hypothesis that chronic Mn neurotoxicity is caused by long-term elevated Mn altering the activity of neuronal cell signaling systems for which Mn normally acts as an essential co-factor that regulate healthy aging. To address this overarching hypothesis we have designed three highly meritorious Specific Aims, namely (1) determine the evolution of genetic pathways altered as Mn exposure extends from acute to chronic, and whether any such effects are persistent after cessation of chronic Mn overload, (2) evaluate the concurrent and persistent functional consequences of acute versus chronic Mn exposures and the influence of neural cell type, neurotransmitter- type, and genetic sex on the magnitude versus types of genetic pathways and functional outcomes altered, and (3) Explore the mechanistic basis of chronic/persistent Mn neurotoxicity phenotypes via metabolic analysis, with pharmacological and genetic manipulation of signaling and metabolic pathways in C. elegans and hiPSC neural model systems. Our highly interactive experimental design brings to bear innovative and complementary expertise to assess shared genetic networks and functional outcomes of Mn-induced chronic neurotoxicity with translation from C. elegans to humans.

NIH Research Projects · FY 2026 · 1998-05

Overall Project Summary The Purdue Institute for Cancer Research (PICR) was established as an NCI basic science cancer center in 1978. The PICR does not treat patients as it does not have a hospital or a clinic. Thus, the PICR focuses on basic science discovery. PICR’s mission is to improve lives by pioneering scientific discovery, developing innovative tools, technologies and therapies to combat cancer, and training the next-generation of cancer researchers. The PICR vision is to make all cancers detectable, treatable and curable. The PICR not only advances basic scientific discovery but also drives the translation of these findings into real-world applications through technology transfer and commercialization. PICR brings together Purdue’s core strengths in disciplines such as Biochemistry, Biological Sciences, Chemistry, Computational Sciences, Engineering, Medicinal Chemistry, Nutrition Science, Pharmacy, Physical Sciences, Structural Biology, and Veterinary Medicine. These foundational areas are integrated into functional, thematic research programs within a transdisciplinary environment, fostering collaborative efforts aimed at developing innovative cancer solutions. As a matrix center, PICR leadership draws on core capabilities through its 93 members from 15 academic departments and 7 colleges across Purdue, to organize an infrastructure based on three Research Programs: Cell Identity and Signaling (CIS), the newly formed Targets, Structures, and Drugs (TSD), and Drug Delivery and Molecular Sensing (DDMS). The PICR expedites the process of discovery by managing six Shared Resources: Flow Cytometry, Computational Genomics, Biomolecular Structure, Life Science Mass Spectrometry, Biological Evaluation, and the Transgenic and Genome Editing Facility. PICR’s Shared Resources offer researchers training and access to advanced technologies for analyzing cells, nucleic acids and proteins; determining detailed molecular structures for drug design; evaluating targets/drugs in vivo; and developing new animal models of cancer. These services are fully integrated into PICR’s collaborative process, enabling novel insights that push the boundaries of cancer science. The PICR fosters a remarkable breadth of cancer research. These include clinical evaluations of dogs with spontaneous malignancies, which serve as a model for drug development and validation. The Institute also explores the fundamentals of molecular motion using interferometry, applying these insights to develop novel cancer therapies. Additionally, PICR uses pioneering mass spectrometry technology that ionizes molecules under ambient conditions to identify cancer markers and monitor chemical reactions in automated synthesis processes. Finally, PICR upholds the Essential Characteristics of a leading cancer center. It offers exceptional Physical Space, robust Organizational Capabilities, and a strong institutional commitment to advancing cancer research. The Institute enables a Transdisciplinary, Collaborative environment with a clear Cancer Focus and is guided by outstanding leadership that drives scientific discovery and progress in cancer prevention, diagnosis and treatment.

NIH Research Projects · FY 2026 · 1996-07

Abstract Aberrant cell signaling stemming from altered protein tyrosine phosphorylation is a major contributing factor to human diseases including cancer. Consequently, anomalous cellular events driven by defective protein tyrosine phosphorylation afford tremendous therapeutic opportunities. Success for such targeted approach is evident by the abundance of protein tyrosine kinase-based therapeutics. Given the reversible nature of protein tyrosine phosphorylation, there is enormous potential to target protein tyrosine phosphatases (PTPs) for disease intervention. However, despite increasing interest in PTPs, they still remain largely an underexploited target class. Among major factors that contribute to the difficulty of PTP-based drug discovery are the lack of understanding of PTPs in disease biology (i.e. insufficient target validation) and challenges in developing PTP- specific small molecule probes for functional interrogation and therapeutic development. The broad, long-term objectives of this program are to define the structure and function of PTPs and to utilize this knowledge to advance drug discovery by targeting them. With the support of this grant in the last five years, we elucidated the oncogenic mechanism by which the PRL2 phosphatase promotes tumorigenesis and established PRL2 as an exciting target for PTEN augmentation therapy. In the next five years, we will focus on SHP1, encoded by Ptpn6, to develop novel cancer immunotherapeutic agents. Although current immunotherapies achieve durable efficacy in some patients, responses for many tumors remain very low. Thus, there is an urgent need for new approaches. To this end, SHP1 is primarily expressed in hematopoietic cells, negatively regulates immune functions and is an intracellular mediator of inhibitory signals transmitted by immune checkpoint receptors. Importantly, SHP1 deletion improves anti-tumor immunity in mice, implicating SHP1 as a promising target for cancer immunotherapy. We hypothesize that potent and selective SHP inhibitors serve as novel immunotherapeutic agents. Unfortunately, no small molecule SHP1 inhibitor exists to demonstrate the translatability of this target. The goal of this proposal is to develop SHP1 inhibitors with the requisite potency, selectivity and drug-like properties to interrogate the therapeutic potential of SHP1 as a cancer immunotherapy target. We have discovered a novel orally efficacious allosteric covalent SHP1 inhibitor (M029), which targets a cryptic Cys residue in SHP1 and selectively inhibits SHP1 phosphatase activity over a large panel of PTPs. Moreover, M029 enhances T-cell activation and exhibits anti-tumor activity in vivo. We will use a focused medicinal chemistry approach guided by computational modeling and co-crystal structures to develop optimized SHP1 inhibitors that can be evaluated either stand-alone and/or in combination with immune checkpoint inhibitors as novel cancer immunotherapy using syngeneic immunocompetent mouse models. These studies serve to pharmacologically validate SHP1 as a new cancer immunotherapy target and provide prototype drugs that can be further optimized for eventual clinical translation.

NIH Research Projects · FY 2026 · 1995-09

The combined active antiretroviral therapy (cART) is critically important for improved HIV management and patient care of HIV-infected individuals. Protease inhibitors (PIs) are important components of cART regimens. The 2020 UNAIDS reports that 38 million people are living with HIV/AIDS in 2019 and over 25 million people were accessing antiretroviral therapy. The cART treatment regimen resulted in a significant reduction of HIV/AIDS-related mortality and greatly improved life expectancies of those patients with access to cART. There is no cure for HIV/AIDS and long-term treatment has posed a serious challenge because of the emergence of multidrug- resistant HIV-1 variants. About 40-50% of those patients who initially achieved favorable viral suppression to undetectable levels experienced treatment failure. These drug-resistant HIV strains can be transmitted, raising further uncertainty with respect to future treatment options. Also, neurocognitive dysfunction, known as HIV-associated neurocognitive disorder (HAND) has become a major concern. Furthermore, PIs are faced with traditional serious limitations including, major toxicity, tolerance, and necessary adherence to complex medical regimens. The development of a new generation of PIs effective against drug-resistant HIV with longer duration of action, and improved CNS penetration properties for treatment and possible prevention of devastating HAND, is vital to the future management of HIV/AIDS. Our highly collaborative research efforts led to the development of darunavir as an approved drug for treatment against drug-resistant HIV and it has emerged as a front line therapy against HIV/AIDS. However, current treatment modalities are far from ideal as an effective long-term treatment option. Based upon X-ray crystal structures of complexes of darunavir or other PIs with HIV-1 protease, we designed and developed diverse classes of potent PIs with marked antiviral activity, and excellent drug-resistance profiles against multidrug-resistant HIV-1 strains. We have also developed tools and important ‘backbone binding’ design concepts to combat drug- resistance. Several recent inhibitors, have consistently shown marked improvement of potency compared to darunavir against a panel of multidrug-resistant HIV-1 variants. These PIs also exhibited much improvement of dimerization inhibitory properties of HIV-1 protease. One of these PIs have potently inhibited integrase function. In our current proposed studies we plan to focus on optimization of the next generation of PIs for clinical development. Our multidisciplinary research efforts integrate structure-based design, synthesis, protein-ligand X-ray crystallography, inhibition kinetics, in-depth virus and cell-biology and pharmacological studies.

NIH Research Projects · FY 2024 · 1991-08

Abstract The overall objective of the project is to contribute fundamental understanding of the exquisitely selective recognition of protein tyrosine kinases for their protein substrates. Selectivity is generated from multiple factors. One factor is spatial localization of the kinase to the proper regions in the cell through docking interactions often mediated by domains independent of the catalytic domain. A second factor is amino-acid sequence recognition of the substrate polypeptide chain near the cleavage site. Protein kinases play a major role in disease and are second to only G-protein coupled receptors for the most targeted protein group for drug development. Among all protein kinases, tyrosine kinases occur most frequently on a list of cancer-driver genes, and are the most clinically targeted to date. The immediate objectives of this project are to 1) achieve a physical rationale for a new entropy-driven allosteric phosphorylation mechanism that regulates tandem SH2 domains of Syk that dock Syk to membrane immunoreceptors; 2) determine if the tandem SH2 domains also serve to localize Syk to cytoplasmic regions in conjunction with newly discovered functionalities of Syk; 3) define the structure of the substrate polypeptide chain existing the C-terminal side of the catalytic site of Src kinase and several other tyrosine kinases in order to evaluate a new perspective on kinase substrate recognition determinants; and 4) identify new tyrosine kinase ligands that are substrate like and interact in the shallow groove where the substrate polypeptide chain binds. To accomplish these objectives, a variety of solution NMR studies will be conducted to characterize molecular interactions, define three-dimensional structure and estimate thermodynamic parameters of tyrosine kinase-peptide substrate and tyrosine kinase- protein substrate complexes. The NMR and biophysical analyses will be tightly integrated with computer simulation methods selected to effectively explore large regions of protein conformational space. Finally, chemical screening using a phosphorylation-based selection with DNA-encoded libraries of high complexity, should identify new substrate-like inhibitor molecules of Src. The expected outcomes will advance scientific knowledge on the physical mechanisms determining selective substrate phosphorylation by these key enzymes in human health. Successful execution of the research plan would also identify small-molecule ligands with potent and selective cellular activity, and impact future efforts to develop molecules useful for studying disease in animal models or for cancer drug development.

NIH Research Projects · FY 2025 · 1991-07

Project Summary/Abstract This application is for a continuing institutional grant designed to provide research training in the area of communication disorders and sciences, for three predoctoral and one postdoctoral trainees per year. Hands-on apprenticeship training is provided in three interrelated areas: (1) Hearing Science; Hearing Disorders; (2) Language Science; Language Disorders and Disabilities; (3) Speech, Swallowing, and Voice Science; Speech, Swallowing, and Voice Disorders. Nineteen active researchers in the Department of Speech, Language, and Hearing Sciences will serve as the participating faculty. These individuals routinely collaborate on projects that cut across these research areas. Advanced coursework will be taken; however, the main purpose of the training program is to provide intensive interactive research experience leading toward the establishment of successful independent clinical investigators. The proposed program focuses especially on the recruitment and training of individuals with a basic science background who wish to pursue research careers in communication disorders, and individuals with a primarily clinical background whose prior research training was minimal. Along with the laboratory research experience, trainees will gain grant experience through a required research grant writing course and the preparation of F31/F32/R21 fellowship applications. Both predoctoral and postdoctoral trainees will be funded for two years. Predoctoral students will be funded before and after their two-year training grant funding through university fellowships, their major advisors’ R01 grants, and, if awarded, individual F31 fellowships. The structure and emphasis of the proposed program should help to address the critical shortage of active and successful researchers in the field of communication disorders and related areas.

Other NSERC · FY 2024

astrodynamics, dynamical systems theory, modelling, simulation, space transportation, trajectory design, n-body problem

Other NSERC · FY 2024

Helmholtz equation, Large cavity, Electromagnetic scattering, Wavelet analysis, Galerkin method, Stability analysis, Nonlocal boundary, Convergence analysis, Bounded domain, High frequency