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NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Due to the progressive depletion of CD4+ T cells, HIV/AIDS patients are more susceptible to infection of Cryptococcus neoformans, an encapsulated fungus that is listed by WHO as a pathogen of critical priority. An estimated 112,000 people die from C. neoformans infections globally each year. C. neoformans is a leading cause of mortality among HIV/AIDS patients. Antiretroviral therapy (ART) can rapidly restore CD4+ T cells in HIV/AIDS patients, representing a major advance in the treatment of HIV-infections. However, the rapid recovery of CD4+ T cells in HIV/AIDS patients that co-infected with C. neoformans after initiation of ART often causes an exaggerated inflammatory response in the central nervous system (CNS), termed immune reconstitution inflammatory syndrome (IRIS). Cryptococcal IRIS is considered as a life-threating condition, as it can lead to a high mortality rate during ART among HIV/AIDS-associated IRIS patients who have a cryptococcal infection. Clinical studies have shown that cryptococcal IRIS is associated with a substantial CNS recruitment of immune cells and enhanced secretions of inflammatory cytokines. However, the cellular and molecular mechanisms involved in cryptococcal IRIS are poorly understood. In particular, it remains to be determined which leukocyte subset(s) and cytokine(s) mediate the death during cryptococcal IRIS and how CD4+ T cell responses are regulated during cryptococcal IRIS. These questions are hard to be answered without animal studies. Using a novel murine model of C. neoformans infection to closely mimic HIV/AIDS-associated cryptococcal IRIS, we will define the mechanisms of cryptococcal IRIS by addressing the following aims: 1) To identify the leukocyte subset(s) accounting for lethal cryptococcal IRIS; 2) To identify the cytokine(s) accounting for lethal cryptococcal IRIS; 3) To identify the factors regulating CD4+ T cells responses during cryptococcal IRIS. Successful completion of this study would gain novel insights into the cellular and molecular mechanisms that mediate lethal immune responses during cryptococcal IRIS and identify potential targets for treatment of HIV/AIDS-associated cryptococcal IRIS patients.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY/ABSTRACT Dynamic interactions between intercellular membranes and the cortical cytoskeleton are critical for cell survival. During their normal functions, cells face physiological and environmental stresses that can lead to rupture of the plasma membrane and/or of the nuclear envelope. Rapid repair of such injuries, whether arising from daily activities or resulting from trauma, infection, or diseases such as cancer, is an active area of cell biology research. My lab has a long-standing track record in successfully identifying key molecules and elucidating their in vivo roles at the cell cortex necessary for the repair of plasma membrane and at the nuclear envelope necessary for repair of the nuclear cortex. The overall focus of the lab is to delineate how cells deal with such cell and/or nuclear cortex disruptions to efficiently and effectively repair the lesions. We have developed a robust inducible single cell repair model using the syncytial Drosophila embryo that has superb amenability for live imaging and genetic tractability that is unavailable in other cell wound repair models. We have also established a model for the newly appreciated nuclear export pathway (Nuclear Envelope budding) on the surface of Drosophila salivary gland and S2 cell nuclei that provides the same superb amenability for live imaging and genetic approaches. While both systems rely heavily on dynamic membrane and/or cytoskeleton/nucleoskeleton interactions, a major challenge in both of these systems is the absence of a molecular outline of the events occurring during the repair and/or export processes in any organism or system. Our goals during the proposed period are to establish the molecular framework underpinning these processes using a combination of state-of-the-art cell biological, genetic, developmental, biochemical, and high-resolution imaging approaches. Our studies are expected to be of significant medical relevance, as understanding the molecules, machineries, and pathways governing cell wound repair, NE-budding (nuclear export), and dynamic membrane-cytoskeleton/nucleoskeleton interactions will be extremely valuable for elucidating fundamental cellular mechanisms, as well as for developing new or enhancing existing strategies for treating conditions associated with cell/nuclear damage, and for disciplines such as regenerative medicine where cell based constructs are used to reconstruct tissues, clinical drug delivery systems where molecules cross cell membranes, and for virus nuclear egress.

NINDS - National Institute of Neurological Disorders and Stroke

Abstract / Project Summary Stroke is a significant contributor to death and disability worldwide. With increased survivability due to advancements in clinical treatments, 35-50% of patients suffer from long-term neurological deficits in learning and memory termed Post-Stroke Cognitive Impairment (PSCI). Utilizing the middle cerebral artery occlusion (MCAO) model of focal ischemia, we can investigate chronic timepoints post-stroke to ameliorate cognitive deficits. Our lab has targeted the transient receptor potential melastatin 2 (TRPM2) channel as a potential locus of therapeutics. As a Ca2+ permeable non-specific cation channel, TRPM2 is activated in periods of oxidative stress, such as in stroke, and contributes to both cognitive and synaptic dysfunction. Indeed, data obtained in the laboratory before I joined demonstrates that acute and delayed administration of a TRPM2 channel antagonist improves synaptic and cognitive recovery following experimental stroke. TRPM2 is in multiple cell- types throughout the brain, and I seek to investigate the neuronal component of TRPM2 by utilizing genetic animal models and adeno-associated viruses (AAVs) to conditionally knockout TRPM2 from neurons. In aim 1, I hypothesize that a neuron-specific knockout rescues long-term potentiation (LTP) and behavioral deficits up to 30-days post-stroke. In aim 2, I seek to investigate the downstream mediators of TRPM2. Data suggests that in periods of hypoxia, a positive feedback loop is initiated; TRPM2 is activated and the kinase PKC is then recruited to the area where it phosphorylates TRPM2 at serine 38 further enhancing activation of the TRPM2 channel. Calcineurin activates (dephosphorylates) glycogen synthase kinase 3-beta (GSK-3) after TRPM2 activation. Evidence shows that dephosphorylated GSK-3 is responsible for the internalization of a-amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors ultimately leading to a decrease in LTP. A final player in this complex signaling pathway is regulator of calcineurin 1 (RCAN1), which binds to calcineurin and increases its activity at key phosphorylation sites. Due to RCAN1’s role within the calcineurin-GSK-3β signaling pathway, RCAN1 is implicated in the bidirectional regulation of hippocampal synaptic plasticity. Data further suggests a potential link between PKC and the downstream actions of RCAN1 are mediated by TRPM2 channel activation. In aim 2, I hypothesize that decreasing RCAN1 and GSK-3 expression will rescue LTP deficits. This training plan will build methodological skills in electrophysiology, biochemical analyses, and more culminating in multiple manuscripts. It will also foster the growth of my career attending seminars focused on women in STEM, networking to further the advancement of women throughout academia, and mentoring the next generation of scientists. I have chosen Dr. Paco Herson as my mentor at The Ohio State University because they maintain incredibly high standards in state-of-the-art facilities that will ensure my development as an academic neuroscientist.

NCI - National Cancer Institute

PROJECT SUMMARY Adaptive mechanisms of resistance are broadly observed across virtually all cancer therapies and contribute to tumor heterogeneity and the emergence drug-tolerant persister cells (DTPs), which limit the upfront efficacy of cytotoxic agents and prevent the full eradication of cancer. KRAS is one of the most commonly observed oncogenic mutations, occurring in approximately 20% of all cancers and at significantly higher rates in pancreatic (~ 75%), colorectal (~40%), and non-small cell lung cancers (~27%). Despite nearly three decades of effort to develop pharmacological agents targeting KRAS, only within the last three years have the first rationally-designed covalent inhibitors for the KRAS G12C mutation been FDA-approved. However, the efficacy has been modest at best, and putative genetic resistance mechanisms have been identified in only ~45% of patients, suggesting that a large percentage of KRAS-driven tumors exhibit innate, non-genetic mechanisms of resistance to these inhibitors. Understanding these adaptive pathways mediating drug resistance to identify new strategies that improve patient survival in KRAS-driven tumors represents a critical unmet need. To study the biology of DTPs, we conducted a genome wide shRNA enrichment screen and discovered that attenuation of the RhoA-ROCK-myosin IIa axis promotes DTP survival through decreased apoptosis and increased cell cycle arrest. This mechanism appears to be conserved across many tumor types, including KRAS-driven tumors treated with KRAS inhibitors, and may represent a therapeutic opportunity to eliminate the residual persister tumor population. In this proposal, we will focus on KRAS inhibition and build upon these key preliminary findings. In Aim 1, we will determine the functional role of the Rho-A/ROCK/myosin IIa axis in promoting DTP survival post-KRAS inhibition in additional 2D and 3D culture systems. Aim 2 will elucidate the mechanism by which attenuation of MYHIIa promotes increased DTP survival by defining the critical cis-acting domains of MYHIIa and the downstream effector pathways required to promote this survival phenotype. Aim 3 will test pharmacological induction of p53 as a therapeutic intervention to enhance DTP killing in KRAS-driven tumors in vivo and also leverage state-of-the-art single cell, barcode tracking to interrogate the origin and transcriptome of DTPs. These studies will 1) provide new biological insight regarding a previously unappreciated link between cytoskeletal regulation, p53 signaling and cellular survival, 2) deploy promising, novel drug combinations specifically targeting the tumor persister population based on biomarker selection, and 3) identify new therapeutic targets for KRAS-mutant tumors to improve clinical responses and patient survival.

NIGMS - National Institute of General Medical Sciences

Summary Given the central role of mitochondrial dysfunction in disease and accumulating data linking peroxisomal dysfunction with disease development, understanding the mitochondrial arm of the UPS and its crosstalk with other organelles, such as peroxisomes, is critical. With current trends toward the aging population, developing therapies for these diseases is a critical need. Strategies primarily aimed at neutralizing toxic reactive oxygen species (ROS) have only partially succeeded. Thus, new treatment options with independent modes of action are needed to improve the success rate of current therapies. The proposed work directly responds to this need and will provide critical insights into the regulation and function of mitochondrial and peroxisomal quality control and biogenesis pathways. Extensive evidence supports the vital role of the ubiquitin (Ub) proteasome system (UPS) in mitochondrial function. Mitochondrial ubiquitination requires factors, such as the prototypical outer mitochondrial membrane (OMM) E3 Ub ligase MARCH5, that uniquely target many mitochondrial pathways. Our new data indicate that MARCH5 activity is also vital for peroxisomes. These organelles host diverse oxidative reactions and play an essential role in fatty acid β-oxidation to generate energy intermediates for ATP production by oxidative phosphorylation (OXPHOS). The preliminary data also show that a subset of MARCH5 localizes to the peroxisomes and controls the abundance of peroxisomal proteins, peroxisome size, and maturation. We will investigate the role of MARCH5 in the biogenesis of mitochondria-derived pre-peroxisomes and in protecting mitochondria against the toxic effects of abnormal accumulation of peroxisomal proteins in the mitochondria when peroxisome biogenesis is defective. A model that we recently developed in which cells exclusively rely on oxidative phosphorylation (OXPHOS) for ATP generation shows that bioenergetic shift from glycolysis to OXPHOS induces (i) degradation of MARCH5 client proteins associated with (ii) increased expression of the OXPHOS proteins, (iii) enhanced capacity of mitochondria to generate ATP, and (iv) proliferation of peroxisomes. These changes were reduced in MARCH5-/- cells and differently affected by distinct MARCH5 mutants. We will test the central hypothesis that, through its mitochondrial and peroxisomal functions, MARCH5 controls the metabolic adaptation of the cell to varying energy substrates. We combine biochemical, state-of- the-art imaging, and gene editing methods to address the following questions: (1) What is the role, cofactors, and mechanism of MARCH5 in peroxisomal biogenesis? (2) What domains and cofactors control MARCH5 specificity toward distinct mitochondrial and peroxisomal proteins and modes of protein degradation? (3) How, through MARCH5 activity, does the bioenergetic status of the mitochondria control cellular energy balance and sensitivity to cell death in healthy cells and cells from "peroxisome-biogenesis" disease-affected patients?

Media Alliance, Inc.

to create the NATURE Lab Urban Environmental Education Center, a critical resource for the North Troy Art, Technology and Urban Research in Ecology Program.

Media Alliance, Inc.

to create the NATURE Lab Urban Environmental Education Center, a critical resource for the North Troy Art, Technology and Urban Research in Ecology Program.

City-As-School High School

Conversion of adjacent 4th floor spaces into a state of the arts Media Lab Space. Modify the fourth-floor library space into a multimedia and mulitmodal Media Commons to serve as a stdent-sentered space for collaboration and critical thinking. Upgrade audiovisual and lighting for the basement-level auditorium into the CAS Media Center for the exhibition of work.

Spark Media Project

Media Arts Studio Space

Seattle Hip Hop Youth Council

African-American youth in Central and Southeast Seattle will learn to create media using new digital arts, audio and video technologies in collaboration with artists and professionals.

Freeway Park Association

Freeway Park Association seeks funding to support three complementary projects happening in Freeway Park Dec 24-June 25. We will illuminate pathways with heritage tree lighting; illuminate art and create connections with a community festival; and illuminate history with shared stories and educational signage. The projects include 1. Foundational winter lighting for public delight and much needed safety, and to create a backdrop for our March art activation; 2. An illuminated art event in March entitled `Meeting at the Balance` supporting 6-9 artists/artist teams' art installations, performances, and art making workshops; 3. Creating public education materials about the social and political history of the park and the details of the Park's renovation which is slated for May 25. Meeting at the Balance will energize and illuminate the park, empower and fund local artists and also educate the community about the future and past of Freeway Park at this moment of expansion and change.

206 Zulu

During President's Day weekend of 2019, 206 Zulu will host the Meeting of the Minds Community Arts Forum at historic Washington Hall,153 14th Avenue. This weekend of intensive programming will bring together local leaders, artists, youth, families and nationally recognized pioneers in urban arts activism. The free community showcase will include guest speakers, panels, presentations, art displays and performances from both emerging and established musicians, artists and dancers.

OD - NIH Office of the Director

Project Summary The proposed application aims to establish the “Meharry Research Facilities for Advanced Genomics” (MeRFAG) at Meharry Medical College (MMC), an Institution of Emerging Excellence (IEE) in the southern United States dedicated to educating healthcare professionals and biomedical scientists with a focus on addressing health disparities. The proposed MeRFAG will serve as a state-of-the-art research environment, attracting high-calibre committed genomics scientists, fostering cross-fertilization of ideas, innovation and interinstitutional collaboration to advance biomedical and translational research. MeRFAG will enhance MMC’s partnerships with academic and industry collaborators, including the genetics-focused Visiting Scientists Program with the Icahn School of Medicine at Mt Sinai, NY, genomic studies through the Diaspora Human Genomics Institute (DHGI) incorporated by MMC, and the NHGRI-funded Center for Genome Research at MMC. It will also support the Together for CHANGE (T4C) initiative, a ten-year project to recruit 500,000 volunteers of African ancestry for a biobank to advance health studies. In keeping with demands for the diverse genomics workforce, T4C will also develop STEM mentoring pathways for capacity building, such as the DNA Learning Center in collaboration with Cold Spring Harbor Laboratory and a Genetic Counseling Training Program. The T4C initiative governed by DHGI is funded by the Regeneron-led biopharmaceutical consortium. In keeping with demands for the diverse genomics workforce, T4C is developing STEM mentoring pathways for genomics capacity building. Additionally, MeRFAG will complement MMC’s partnership with the Chan Zuckerberg Initiative to Accelerate Precision Health, which is recruiting faculty in MMC’s new department of Integrative Genomics to focus on clinical and basic genomics to address disease etiology and treatment. MeRFAG will also strengthen national programs like the Meharry- led Southeast Hub of NIH AIM-AHEAD program and the DoE-funded TSU-MMC-Fisk alliance, aimed at building competitiveness in diverse workforce. Approximately 17,898 sq ft of unused space will be renovated to house a cluster of eight research core facilities in the proposed MeRFAG with distinct capacities of a Biorepository, Digital Pathology, Transcriptomics, Pharmaco & Toxicogenomics, Microbial genomics, Mitochondrial genomics, Immunogenomics and Immune cell therapy, and Single Cell Sequencing and NGS. These facilities will enable a broad scope of cutting-edge genomics research addressing health disparities, reduce startup costs for new faculty, and attract high-caliber researchers. By integrating innovative research capabilities, MeRFAG will position MMC and middle-TN as a leader in genomics-driven healthcare research.

City of Seattle — Neighborhood Matching Fund

Implement series of community-supported road safety and placemaking measures (e.g. pedestrian lighting, distinctive paving, crosswalks, signage, and art) recommended in an NMF Small & Simple-funded conceptual plan.

NYC Department of Cultural Affairs

Mencius Society for the Arts, Inc.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY The kinase Akt is a central mediator of insulin signaling. Its activation by insulin occurs when Akt is phosphorylated at two canonical sites, T308 and S473. Other covalent posttranslational modifications also contribute to Akt regulation, such as phosphorylation at alternative residues, acetylation, and ubiquitination. In this grant, we investigate a distinct mechanism of Akt activation: controlled access to a manganese (Mn2+) ion. Mn is an essential trace element that is acquired through the diet and excreted primarily via efflux from hepatocytes into bile. The efflux of Mn is mediated by the canalicular transporter Slc30a10. We have found in mice, cells, and in vitro that increased Mn availability directly promotes Akt activity in hepatocytes, in a manner that does not require upstream insulin signaling. The Mn-induced activation of Akt is sufficient to suppress glucose production, which provides a biochemical explanation for longstanding observations that Mn has glucose-lowering effects in humans and mice. Moreover, we have found that Mn availability is regulated nutritionally, via carbohydrate signaling. In this grant, we will use classic and state-of-the-art biochemical tools to investigate the cellular and biophysical features of the interaction between Akt and Mn. We will furthermore use genetic and dietary interventions in mice to investigate how control over Mn availability contributes to normal physiology and states of overnutrition. Success of this work will reveal a novel mechanism of regulating Akt activity and hepatic glucose production and generate new avenues for research in metabolism and cell signaling.

NIA - National Institute on Aging

SUMMARY Metals are neurotoxic at high doses yet can contribute to motor and cognitive deficits even at environmentally relevant doses. Metals contribute to amyloid β misfolding and tau hyperphosphorylation, which are pathological hallmarks of Alzheimer’s disease (AD) and AD-related dementia (ADRD) risk as well as cognitive decline. Metals also interact with the APOE4 allele to influence AD risk, advance neurodegeneration, and have vascular effects that may further contribute to dementia risk. Metals may thus represent multiple hits for risk of cognitive impairment and dementia. Yet, few cohort studies have comprehensively evaluated the association of metal exposures with mild cognitive impairment (MCI) and AD/ADRD. To fill this knowledge gap, we propose to leverage the NIH-funded Atherosclerosis Risk in Communities (ARIC) and Multi-Ethnic Study of Atherosclerosis (MESA) cohorts of diverse US adults to test the hypothesis that widespread exposure to metals—determined by established and novel biomarkers—is associated with MCI and AD/ADRD risk and with key pathophysiological processes that explain this risk. ARIC and MESA have rich biorepositories, as well as examination, laboratory, omics and clinical data. In these unique and diverse cohorts, we propose to add a metallome profile to quantify metal exposure and internal dose for each participant by measuring metals in urine, blood, and serum at repeated visits in all participants, as well as in brain-derived extracellular vesicles in a subset of participants. Priority metals include lead, cadmium, copper, mercury, manganese and zinc, although other metals will also be measured. We will connect these metallome profiles with rich brain health and multi-omics data (whole genome sequencing, epigenomic/methylomic, transcriptomic, proteomics, targeted and untargeted metabolomics). We will use powerful, state-of-the-art analyses to determine the prospective associations of long-term metal exposures with risk of cognitive decline, MCI and AD/ADRD risk (Aim 1), and with the trajectory of plasma AD and brain imaging biomarkers (Aim 2) in diverse US adults overall and by sex, race/ethnicity, and APOE4 genotype. We will then develop a predictive multi-omics fingerprint that quantifies risk of MCI, AD/ADRD, and cognitive decline due to metal exposures (Aim 3). Because metal exposures are preventable and treatable, adding high-quality measures of the metallome profile to diverse cohorts with longitudinal brain health and extensive omics data will enable this project to contribute key knowledge of the molecular/biological pathways involved in development of cognitive decline as well as identify new targets for the prevention and treatment of AD/ADRD. This work will generate critical knowledge and serve as a robust model for generating highly valuable data that can be leveraged to prevent/mitigate harmful metal exposures and protect cognitive health.

Metcalf Foundation

The Metcalf Foundation supports performing arts innovation, environmental programs, and inclusive local economies in Ontario.

NSF

Large language models (LLMs) are advancing the state of the art in nearly all areas of artificial intelligence, yet they remain poorly understood. At a time when new abilities as well as new limitations of LLMs are continually coming to light, a clear understanding of what they can and cannot do (that is, their expressivity) is becoming increasingly important. Furthermore, differentiating between the tasks that LLMs can solve at all scales, and those that LLMs can solve at small scales but are guaranteed to fail on at larger scales can be central to the success of some applications of LLMs, particularly where safety guarantees are needed. These questions can be answered with certainty only by mathematical verification. This project is contributing to the study of connections between LLM expressivity and mathematical logic. It is using those connections to reap both theoretical and practical benefits, in the form of new guarantees for LLMs, new extensions of LLMs, new methods for explaining how LLMs work, as well as new developments in mathematical logic. Just as the Curry-Howard isomorphism established a deep connection between logic and programming languages that enabled many results to be exchanged between the two fields, we are developing a "Curry-Howard isomorphism for neural networks": not merely a connection between one kind of neural network and one logic, but a correspondence between the elements of neural networks and the elements of logic that leads to a rich exchange of ideas between the two fields. This connection is establishing new theoretical results about neural networks and driving the development of new neural networks. In the other direction, the proposed research program is pursuing new and exciting developments in logic and model theory, particularly at the intersection of finite model theory and continuous logic, which has not been previously studied. The project is creating interdisciplinary collaborations, not only within the project itself but also between researchers in logic and deep learning more broadly. 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

With this award, the Molecular Foundations for Biotechnology (MFB) Program is funding Dr. Oded Regev from New York University (NYU) and Dr. Jef Boeke from NYU Langone Health to develop a novel experimental method (PolySnap-seq) to probe the positions of ribosomes along individual RNA molecules. Ribosomes are molecular machines that produce proteins by “walking” along RNA and reading the instructions written in it. Despite being critical for life, it is currently not clear how ribosomes organize along an RNA molecule during gene expression. Are they equally spaced along the RNA molecule or do they cluster to form “convoys”? Do they maintain a safe distance from each other or pile up in “traffic jams”? The experimental method uses an enzyme to modify the bases of RNAs that are not protected by the ribosomes, thereby allowing researchers to take a snapshot of the simultaneous positions of all ribosomes along an RNA molecule. As such, the method provides novel insights into ribosome collective behavior and enables new biotechnology applications to, for example, optimize gene expression. This project provides graduate students and postdoctoral fellows with specialized training in method development, data analysis, and machine learning. Finally, an outreach component uses “yeast art” to introduce the general public to biotechnology. The efficiency in which ribosomes translate mRNA into proteins is affected by a complex regulatory logic encoded in RNA sequence and structure. Understanding this logic is required for the rational design of RNA transcripts in biotechnology. Powerful tools like ribosome profiling revolutionized our understanding of how ribosomes are affected by RNA features. Yet, many fundamental questions related to translation remain elusive, such as the minimum separation between ribosomes, the extent of burst translation, and the effect of single nucleotide variants. This research project will develop PolySnap-seq, a novel method for probing in bulk the simultaneous positions of all ribosomes along individual transcripts using an adenosine deaminase enzyme and long read sequencing to identify stretches of mRNA that are not occupied by ribosomes and, therefore, can be efficiently modified to inosine bases. The method will provide detailed transcriptome-wide information on translation, including the separation between ribosomes, how such spacing depends on the distance from the translation initiation site, and the effect alleles and isoforms have on ribosome profiles. 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

With this award, the Molecular Foundations for Biotechnology (MFB) Program is funding Drs. Chaolin Zhang and Harris H. Wang from Columbia University to engineer modular proteins that can be programmed to precisely edit sequences of RNA messages or control the expression of genes encoded in these messenger RNAs in human cells. This project adapts a unique class of plant proteins, called pentatricopeptide repeat (PPR) proteins that naturally recognize RNA sequences through a modular code. Such proteins will overcome limitations of current RNA-targeting technologies, including imprecise binding and difficulties in introducing them into cells. PPR proteins will be custom designed to bind specific RNA targets with high accuracy, and their performance tested in human cells and compared to existing technologies. In parallel, the project will include community outreach and education through workshops hosted with a public biology lab in New York City, offering hands-on experiences in RNA biology and biotechnology to citizen scientists. Overall, this work could lead to powerful new RNA-based tools with broad applications in biotechnology, agriculture and medicine, while also promoting public understanding and engagement with cutting-edge biological science. The technical goal of this research is to establish a versatile and high-performance platform for programmable RNA targeting using engineered PPR proteins. The team will apply computational approaches to decipher the natural code that allows PPR proteins to bind specific RNA sequences, and then use synthetic biology and high-throughput screening to optimize designer PPR variants (dPPRs) for use in human cells. These tools will be evaluated in terms of binding specificity, efficiency, and functional versatility, and benchmarked against state-of-the-art RNA technologies such as CRISPR and RNA interference. The project integrates computational modeling, synthetic DNA assembly, and RNA functional assays to explore the full potential of PPR-based RNA engineering. By addressing key technical limitations of current platforms—such as off-target effects and delivery complexity—this research will significantly advance molecular tool development. It also offers new insight into how modular RNA-binding proteins function, which may inform future efforts to engineer RNA recognition in diverse biological systems. This project is supported by the Division of Chemistry in the Mathematical and Physical Sciences Directorate, by the Division of Molecular and Cellular Biosciences and the Genetic Mechanisms program in the Biological Sciences Directorate and by the Division of Information and Intelligent Systems in the Directorate for Computer and Information Science and Engineering. 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.

The Municipal Art Society of New York

Michael Gotkin - Gotkin: WALKING TOURS OF MODERN ARCHITECTURE IN NEW YORK CITY

Michigan Theater Foundation Inc

Michigan Theater Foundation Inc is an active grantmaking foundation based in Ann Arbor, MI. Focus: arts. Contact the foundation directly for current funding opportunities.

New York Folklore Society

Mid Atlantic Arts Foundation Services to New York State