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Fondation Carasso

Supports sustainable food systems and citizen art in France and Spain. Focus on ecological transition and cultural inclusion.

Fondazione Cariplo

Milan-based banking foundation distributing 150M+ EUR annually for environment, art, research, and social services.

Fonds de recherche du Québec

FRQSC funds research and training in social sciences, humanities, arts, and letters in Quebec.

Ford Foundation

Grants for arts organizations and artists challenging narratives and advancing social justice through creative expression.

National Park Service

Produce four main-stage productions featuring Americana; daily offerings of the one act play One Destiny highlighting first person accounts leading up to Lincoln s assassination at Ford s Theatre; teacher and student workshops featuring America s past while revealing meaningful connections to today; teacher summer institutes; on-line learning programming including virtual field trips.

Language Line Services Inc. D/B/A Language Line Solutions

Editorial and Design and Graphic and Fine Art Services

Foundation for Enhancing Communities

Foundation for Enhancing Communities ($100M in assets) supports nonprofits in PA through grants focused on education, community development, arts, health. Awards range from $1,000 to $50,000.

Freeway Park Association

The Freeway Park Association will be hosting a four season art installation that will be held at Freeway Park located at 700 Seneca Street. The Four installations are: Winter 2022 light-art installation starting in December 2022, Spring Freeway Park Bloom starting in June 2023, Summer Fountain Fest starting in July 2023 and culminate with Fall Fest starting September 2023. The event is free and open to the public.

NEI - National Eye Institute

The ocular lens serves as an excellent model for studying cell fate determination, as it consists of two distinct cell types derived from the surface ectoderm: lens epithelial and fiber cells. Lens development requires suppression of pro-neurogenic pathways, distinguishing it from other anterior placodes, such as the olfactory placode, which gives rise to neurons. Mutations in key transcription factors (TFs), including AP-2α, FOXE3, and PAX6, lead to overlapping developmental defects such as aphakia, incomplete lens separation, and fiber cell abnormalities, suggesting shared transcriptional targets and regulatory mechanisms. However, a major gap remains in understanding how FOXE3 functions as a transcriptional regulator and how its activity influences chromatin architecture to suppress pro-neurogenic gene expression during lens formation. Preliminary studies using CUT&RUN identified a de novo FOXE3-binding motif, with strong similarity to FOXD3, and revealed that FOXE3 is required to repress neurogenic gene expression in early lens cells. Additionally, RNA-seq analyses of Foxe3 mutant lenses demonstrated significant differential gene expression linked to pro-neurogenic pathways. This led to the hypothesis that FOXE3 functions as both a transcriptional activator and repressor, coordinating chromatin remodeling to establish and maintain lens cell identity. To test this, state-of-the-art chromatin and transcriptomic technologies, including single- nucleus multiomics (ATAC-seq + RNA-seq), CUT&RUN, and functional assays in chick embryos, to dissect FOXE3’s molecular mechanisms will be conducted. Aim 1 will identify FOXE3 transcriptional targets and determine how chromatin accessibility (DARs) and FOXE3-bound enhancers and promoters are altered in Foxe3 mutant lenses. This will be accomplished through the integration of single-nucleus multiomics and CUT&RUN data to map the FOXE3-dependent regulatory landscape. Aim 2 will determine the functional role of FOXE3 in cell fate decisions by (1) gain and loss of function assays in chick lens cells, (2) testing its ability to suppress neurogenesis in the developing chick retina, and (3) identifying FOXE3-interacting proteins via immunoprecipitation and mass spectrometry. The completion of these aims will provide mechanistic insights into FOXE3’s role in lens development, establish a FOXE3 DNA-binding motif, and identify targets of FOXE3 regulation. These studies aim to reveal how FOXE3 mutations contribute to congenital eye disorders such as aphakia, cataracts, microphthalmia, coloboma, and Peters anomaly. By elucidating the chromatin regulatory mechanisms underlying lens cell identity, this work has the potential to inform therapeutic strategies for human eye diseases linked to transcriptional dysregulation.

Path with Art

Path with Art's purpose for this project is to utilize the power of art to build community and to foster restoration for those who have experienced trauma. The project is two-fold: hold workshops to design, create and install five `Free Little Art Galleries`(FLAG's) and provide 100 free art kits at each site for community members. Each FLAG will be placed near Path With Art's social service partners (Yesler Terrace, DESC, Plymouth Housing, KC Drug Diversion Court, and Sound Health) in underserved neighborhoods creating low-barrier entry opportunities for art exploration, inner healing, and joyous connection. At the culmination of the project, an exhibition of all collected art works will be held at the Seattle Center. The anticipated project completion date is 11/30/2022

Hunger Intervention

Hunger Intervention Program (HIP) is partnering with Lake City Farmers Market to offer free, fun activities for children. These include arts and crafts, science exhibits, and other STEM activities. In addition, HIP will also offer cooking demos and nutrition tips at the farmers' market to showcase fresh, seasonal produce from the market. The activities are in conjunction with HIP's Summer Meals program, which addresses food insecurity and promotes healthy eating for children under the age of 18 who are at risk of going hungry when schools are closed for the summer. This year, HIP is serving summer meals at twelve locations, including the Lake City Farmers Market, which runs once a week on Thursdays. This funding request is specifically for activities at the Lake City Farmers Market for the month of August, September, and October (up to ten market days). This funding will not be used for the summer meals program.

Fremont Arts Council

On Saturday June 18, 2022 at 2pm starting at 3rd Ave NW and NW 39th St and ending at N 35th St and Evanston Ave N. The Fremont Arts Council will be hosting the 32nd Fremont Solstice Parade. The parade will include 60 community-based, people-powered ensembles parade down the streets of Fremont with giant puppets, stilt walkers, floats, dancers, cyclists, and musicians in this kaleidoscope of joyous human expression. The event is free and open to the public. This contract will be complete by the end of July.

Fresno Regional Foundation

Fresno Regional Foundation ($150M in assets) supports nonprofits in CA through grants focused on education, health, arts, community development. Awards range from $2,000 to $75,000.

NIDA - National Institute on Drug Abuse

This K24 Midcareer Investigator Award in Patient-Oriented Research (POR) will provide protected time for Oluwaseun Falade-Nwulia, MBBS, MPH, Associate Professor of Infectious Diseases at Johns Hopkins University, to expand a structured, sustainable mentoring program for trainees and early-stage investigators committed to improving health outcomes for people who use drugs (PWUD). Dr. Falade-Nwulia is a clinicianscientist with expertise in infectious disease and addiction care whose research applies implementation science to identify determinants of care engagement and to design, implement, and evaluate strategies that increase uptake of evidence-based interventions; including HIV pre-exposure prophylaxis (PrEP), antiretroviral therapy (ART), direct-acting antivirals (DAAs) for hepatitis C virus (HCV), and medications for opioid use disorder (MOUD). Her mentoring portfolio focuses on investigators whose work addresses the intersecting epidemics of HIV, HCV, substance use disorders (SUD), and overdose among PWUD. Through this K24, Dr. Falade-Nwulia will expand mentoring in POR that integrates behavioral economics, implementation science, and economic evaluation to improve uptake and continuity of care within integrated HIV and SUD care models. Mentoring activities will include longitudinal career development planning, structured works-in-progress sessions, and collaborative research engagement. The mentoring aims are: (1) to develop the next generation of independent physician-scientists and health services researchers equipped to conduct rigorous POR focused on PWUD, and (2) to establish the Nudging Integrated Care and Engagement (NICE) Program, a structured mentoring platform that leverages the robust research and training infrastructure of the Johns Hopkins University School of Medicine and the Bloomberg School of Public Health. The K24-supported research platform will advance the field by: (1) integrating behavioral-economics-informed implementation strategies (e.g., defaults, friction-reduction, incentives, commitment devices, and socialinfluence approaches) into existing service delivery models to address behavioral drivers of under-utilization of HIV prevention and SUD treatment among PWUD; and (2) conducting rigorous mixed-methods and costeffectiveness evaluations to generate scalable, policy-relevant strategies. This award will also allow Dr. Falade-Nwulia to obtain advanced training in behavioral economics and economic evaluation, further enhancing her POR program and capacity to mentor early-stage investigators. Ultimately, this K24 award will accelerate the development of a skilled workforce focused on improving HIV and SUD outcomes among PWUD, while advancing implementation science to optimize integrated care delivery in community-based and rural settings in Maryland and beyond.

NIBIB - National Institute of Biomedical Imaging and Bioengineering

Applications of brain Positron Emission Tomography (PET) have been in place for over 40 years. The combination of quantitative PET systems with novel radiotracers has led to numerous imaging paradigms for understanding normal and pathological brain physiology and pharmacology. Brain-dedicated PET systems offer important advantages over currently available PET systems in terms of sensitivity and resolution. Funded by a BRAIN Initiative grant, we developed the NeuroEXPLORER (NX), an ultra-high performance brain PET system. To date, human results have produced exceptional image quality and the delineation of small brain nuclei. The system's performance derives from its long axial field of view, small crystal elements, depth of interaction measurement, and excellent time-of-flight resolution. This proposal takes the next steps to optimize system performance including accuracy and precision, expand on the capabilities for dynamic PET with tracer kinetic modeling, and demonstrate the real-world performance with a wide range of PET radiopharmaceuticals. The proposal includes the following Aims. Specific Aim 1: Optimize key aspects of the system performance and reconstruction methodology to maximize image quality and minimize noise. We will further optimize and improve rigid and non-rigid motion correction, investigate impact of detector crosstalk and corrections, and develop reconstruction methods with practical computation times. Specific Aim 2: Develop and extend the capabilities of the NX for dynamic analysis using tracer kinetic modeling. Our initial assessment of extracting image-derived input functions from the carotid arteries has been very successful, and we will further validate this approach against arterial blood samples with a large cohort study using multiple radiopharmaceuticals that are commonly used in research and have potential clinical impact. We will also develop and validate methods to estimate the radiopharmaceutical metabolite corrections using population modeling and kinetic analysis strategies. In addition, the ultra-high resolution and sensitivity of the NX allows the reassessment of optimal modeling methods, which will be explored for tracers with challenging spatiotemporal distributions. Specific Aim 3: Real-world performance of human brain scans. We will further develop our 3D printing methods to generate a full-brain phantom and use it to compare to other PET systems. We will facilitate access of this phantom to other sites with novel brain PET systems. To truly optimize NX human imaging, we will perform test/retest studies with multiple radiopharmaceuticals and compare NX images to those of a current state-of- the-art whole-body system (Siemens Vision). This work will demonstrate the significance of the NX's performance characteristics and enable harmonization with conventional PET/CT scanners. In addition, we will perform brain activation studies using functional PET in a paradigm targeting the olfactory system, which is highly relevant in the early manifestations of neurodegenerative disorders.

OD - NIH Office of the Director

The goal of this S10 Instrumentation Grant application is to acquire a state-of-the-art Cytek® Aurora Full Spectrum 5-laser with automated sample loader flow cytometer for the Flow Cytometry and Cell Sorting (FCCS) Core Facility at the Tulane University School of Medicine (SOM), housed and administered in the Department of Microbiology & Immunology. This instrument will support the research of a minimum of 12 NIH-funded investigators at Tulane SOM and serve as a research and educational resource for regional investigators. The Tulane SOM is an NIH-supported institution with a mission that integrates research, training and service in biomedical research to improve human health through basic and applied biomedical research. In this application we present research projects from 10 Major users and 3 Minor users whose work is performed at the Tulane SOM. These projects are focused on infectious diseases, immunology and inflammation, which are areas of expertise at Tulane SOM. This work attracts national collaboration. Each of the profiled users has a strong history of NIH funding and needs for advanced flow cytometry technology. The existing Cytek® Aurora (3 laser, 38 parameter) and BD LSRII (4 laser, 13 detectors) flow cytometer cell analyzers have been in continuous operation for a nearly decade. While these instruments were state-of-the-art when purchased, they are no longer sufficient to meet future needs with respect to high parameter capability, resolution and versatility. We propose purchasing a Cytek® Aurora equipped with an ultraviolet, violet, blue, yellow/green, and red laser permitting detection of 64 parameters and a high-throughput system. The Cytek® Aurora offers several advantages over our existing instruments to meet investigators’ future needs. The inclusion of multiple lasers ensures addition of at least 20 more parameters than are possible with our existing flow cytometry analyzers, which can detect up to 38 and 13 parameters respectively. Compared to other premiere systems on the market, the Cytek® Aurora offers the best overall system in terms of number of parameters, service and price. The availability of a high-parameter and versatile instrument such as the Cytek® Aurora is expected to attract additional investigators that require this technology, leading to new collaborations that will expand the scope of research at the Tulane SOM and the greater New Orleans area.

NIDCR - National Institute of Dental and Craniofacial Research

ABSTRACT Amyloid was identified in the context of pathology but does not always represent aberrant protein folding. Functional amyloid is now recognized in all kingdoms of life. Amyloid aggregates possess evolutionarily conserved cross -sheet quaternary structures with common biophysical properties enabling their detection and study. Microorganisms are now known to produce purposeful amyloid within biofilm environments, but, considering their prevalence, little is known regarding molecular events influencing amyloid formation. Dental caries is a biofilm-dependent disease caused by dysbiosis and overgrowth of acidogenic and aciduric bacteria, particularly Streptococcus mutans. Amyloid is observed in vivo within dental plaque. Our group was first to discover oral amyloids, and we have identified four amyloid-forming proteins in S. mutans. P1 (AgI/II), WapA, and Cnm are sortase-localized adhesins and virulence factors. The fourth protein, Smu_63, negatively regulates biofilm cell density and genetic competence. Extensive tertiary and quaternary structural characterization of P1 is in hand, with characterization of the other proteins underway. Our X-ray fiber diffraction evidence proved a classical stacked -sheet amyloid structure for S. mutans amyloids, and our work revealed a new paradigm for multiple streptococcal and staphylococcal amyloids in that naturally occurring adhesin truncation products play two key roles within the organisms' biofilm life cycles. First, in monomeric form by promoting adherence to cognate ligands via quaternary interactions involving the cell surface-linked parent proteins, and second in amyloid form by quenching adhesive function and apparently facilitating detachment of aging biofilm cultures. The left-handed Z-conformer of extracellular DNA was recently associated with bacterial biofilm stability whereas right-handed B-DNA is associated with detachment. Of interest, the amyloid but not the monomeric form of neuropathologic A drives conversion of Z- to B-DNA. Also, membrane lipids impact amyloidogenesis by an unknown mechanism. Cardiolipin-rich mitochondrial membranes modulate amyloidogeneis of Parkinson and Huntingtin Disease-associated -synuclein and Htt, respectively. Cardiolipin is a prevalent anionic lipid in S. mutans cytoplasmic membranes and extracellular membrane vesicles, particularly under stress conditions. In this application we will define reciprocal mechanistic influences of amyloid-forming proteins on B- and Z-forms of DNA in vitro and in vivo in mono- and multi-species biofilms (Aim 1), determine the impact of membrane lipid composition on amyloid levels during biofilm progression and assess mechanistic interactions of specific lipids of interest on amyloidogenesis of known virulence-associated proteins (Aim 2), and continue to use state-of-the-art methods including solution and solid-state NMR spectroscopy to identify and characterize structural transitions reflective of monomer to amyloid conversion and determine changes in amyloid signatures for each protein upon exposure to different DNA conformers, amyloid-modulatory lipids, and other amyloidogenic proteins (Aim 3).

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

PROJECT SUMMARY/ABSTRACT Assisted reproductive technologies (ART) have revolutionized fertility treatments, yet implantation success rates remain suboptimal. Emerging evidence reveals that maternal tubal fluid, specifically extracellular vesicles (EVs), nanoscale membrane-bound carriers rich in bioactive molecules that play a pivotal role in embryo-maternal communication essential for early embryo development and implantation. EVs transport lipids, proteins, and regulatory RNAs, including miRNAs, which influence embryo physiology and developmental competence. Although in vitro studies demonstrate embryo uptake of EVs from reproductive tract cells across species, the physiological relevance of maternal EVs during natural embryo development in vivo remains largely unexplored. Critically, EV populations and cargo profiles differ markedly between in vivo and in vitro conditions, underscoring a pressing need to investigate EVs in their native environment. Our innovative study leverages oviductal epithelial cell-specific CD9-green fluorescent protein (GFP) reporter mice to directly visualize and track maternal EVs within preimplantation embryos in vivo. We have discovered CD9-GFP+ EVs localized in the perivitelline space of 4- to 8-cell stage embryos, providing the first direct in vivo evidence of maternal EV-embryo communication during early development. Building on this, our research pursues two complementary aims: (1) to comprehensively map EV distribution and profile miRNA cargo in oviductal and uterine luminal fluid throughout early pregnancy stages, illuminating dynamic changes in EV-mediated signaling; and (2) to elucidate the functional significance of epithelial cell- derived EVs by employing pharmacological inhibitors to disrupt EV biogenesis and release in vivo, assessing consequent effects on embryo development, implantation, and pregnancy outcomes. This study offers a significant advance in reproductive biology by uncovering the in vivo role of maternal EVs in supporting embryo development and implantation. Our innovative use of epithelial-specific CD9-GFP reporter mice to directly visualize EV transfer to embryos provides valuable new insight into natural embryo-maternal communication. By combining cutting-edge molecular profiling with functional inhibition of EV biogenesis in vivo, this research is uniquely positioned to identify key EV cargos that influence embryo viability and pregnancy outcomes. The results will deepen our fundamental understanding of early developmental processes and enable the development of novel, clinically relevant strategies to improve assisted reproductive technologies. Leveraging maternal EVs as biomarkers or therapeutic agents holds strong potential to enhance ART success rates and promote healthy pregnancies, addressing critical challenges in fertility treatment.

NIAID - National Institute of Allergy and Infectious Diseases

PROPOSAL SUMMARY Autoimmune diseases remain challenging to treat due to a lack of therapies that specifically target immune dysregulation without inducing generalized immunosuppression. Dysregulated immunoregulatory networks drive autoimmune disorders and are often associated with imbalances in regulatory T (Treg) and effector T (Teff) cells. Treg cell therapy or selective expansion of Treg cells in vivo can shift the Treg/Teff balance towards Treg cells to resolve ongoing inflammation and promote tissue repair to restore function and improve overall quality of life. However, selective and functional expansion of Treg cells during ongoing autoimmune conditions (i.e., therapeutic use) has been challenging. This is mainly because immune regulatory networks are complex, and our knowledge of the cellular and molecular choreography of Tregs in tissues is still evolving, particularly in the context of autoinflammatory disorders of the central nervous system (CNS). Treg cells hold tremendous potential to not only stop the course of the disease but also to restore neuronal function by inducing the repair of damaged axons. Therefore, our main objective is to investigate key principles of expansion of Treg cells to limit the pathophysiology of CNS autoimmunity and promote myelin repair. Capitalizing on the multiphoton imaging, state-of-the-art ratiometric calcium indicator, Salsa6f, label-free detection of myelin lesions, we aim to identify the role of combinatorial activation of T cell receptor (TCR), IL-2 signaling, and TGF-beta signaling for expansion of Treg cells in vivo. Using immunomodulatory Treg expanding biologics (TREBs) and experimental autoimmune encephalomyelitis (EAE), a model of MS-like disease, we will determine target engagement, biodistribution, and immunosafety of combinatorial Treg-expanding biologics (Aim 1); and define cellular and molecular determinants of Treg expansion and evaluate therapeutic efficacy in models of CNS autoimmunity (Aim 2). We postulate that selective expansion of Treg cells is an ideal strategy to curb ongoing autoinflammatory responses while preserving the immune system’s ability to fight new infections and promoting tissue repair for functional recovery. Although our exploratory/developmental project aims to establish a mechanistic link between Treg expansion and clinical improvement during CNS autoimmunity, in a broader context, our studies will guide the rational design of Treg-targeting immunotherapies, accelerating translation into effective and safe treatments for MS and several other autoimmune conditions.

NIMH - National Institute of Mental Health

PROJECT SUMMARY Somatic mosaicism, the genomic differences among the billions of cells in the human brain, may explain the incomplete penetrance and variable expressivity in highly heritable neurodevelopmental disorders. Thousands of clonal somatic mosaic variants (SMVs) in subpopulations of neurons have been discovered in brains of schizophrenia and autism patients, necessitating an urgent, unmet demand to determine if these diverse somatic mutations have a causal role in disease. Major challenges include (1) the inability of using conventional statistical methods for common variants to associate disease status with risk variant, (2) the vast space of non-coding candidates with unknown function, and (3) the unresolved relevant cell types and developmental stages linking mutations to phenotypes. Just as integrating high-throughput genomic-, CRISPR, and stem cell-based technologies resulted in significant progress in understanding germline risk variants, they represent a novel approach to uniquely address the major challenges in the field of somatic mosaicism. As a co-mentored computational and experimental biologist, I will leverage state-of-the-art functional genomic technologies and bioinformatic pipelines to systematically characterize all brain non-coding SMVs discovered to date, resolving their causal roles in neurodevelopmental disorders. From all SMVs identified in case and control brains, I will first create a functional catalog of expression-modulated SMVs in a developmental- and cell-type-specific manner by applying massively parallel reporter assays in human induced pluripotent stem cells (hiPSCs)-derived neural progenitor cells (NPCs) and post-mitotic neurons. By doing so, I will be able to interrogate whether differences in patterns of expression-modulated SMVs exist between cases and controls. Second, I will compare the somatic and germline genetic architectures across neurodevelopmental disorders, determining whether somatic mutations act via the same pathways as germline mutations, or affect genes relevant to diseases, indicating a causal role. By simultaneously uncovering the downstream transcriptomic profiles of hundreds of regulatory elements harboring SMVs with CRISPR screen, I will be able to pinpoint putative disease-causal SMVs. Finally, I will validate the phenotypic impact of putative causal SMVs in physiologically complex and relevant models including 3D brain organoids and “mosaicism-in-a-dish”, testing both cell-autonomous and non-autonomous mechanisms of SMVs. Overall, this work, representing a novel application of scalable functional genomic technologies to SMVs, provides a framework to identify SMVs with putative causal effects in neurodevelopmental diseases, advancing our understanding of a poorly understood disease mechanism. This fellowship will provide me with training encompassing computational genomics, stem cell models and broadly applicable phenotyping techniques, setting a foundation for me to launch an independent research program distinct from my mentors', querying somatic mosaicism's impact into novel cell types, contexts and diseases towards discovering novel therapeutic targets.

NIAID - National Institute of Allergy and Infectious Diseases

The purpose of this contract is to conduct, develop, acquire, improve, implement, validate, analyze and report data from state-of-the-art high-throughput functional omics assays and approaches (e.g., genomics, epigenomics, transcriptomics, proteomics) for comprehensive characterization of immune responses in samples from in vivo or in vitro studies investigating SIV, SHIV, or HIV. The assays will primarily focus on samples from animal models for HIV, however analysis of samples from human clinical trials with HIV may be included to evaluate immunogenicity and efficacy of vaccines or other prevention strategies.

NCI - National Cancer Institute

ABSTRACT Although cancer screening has led to improved detection of early-stage cancers, many cancers can recur and metastasize several years later. In breast cancer, there is a growing and urgent need to develop therapeutics that intercept cancer cells before they invade and disseminate. For instance, although targeted therapies against erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2) have proven highly successful, metastasis is untreatable. Preliminary data reveal how isoforms of HER2 that are associated with treatment resistance and recurrent metastases – e.g. the exon 16 null isoform (..........and the N-terminally truncated isoform (p95) – elicit distinct tumor phenotypes. Our own observations in a mouse model of HER2 isoform heterogeneity demonstrate that p95 HER2 drives early transitions to motile and invasive behaviors prior to detection. This is in stark contrast to ........or wild-type HER2 (WT)-driven murine mammary cancers that proliferate and are generally detectable prior to invasion. Thus, understanding how HER2 isoforms signal in vivo could provide new opportunities for preventing or treating metastatic breast cancers. The objective here is to determine how isoforms of HER2 can drive distinct tumor cell behaviors. The significance of this application is that it will provide molecular signaling mechanisms explaining how ........ and p95 control ‘go’ and ‘grow’ decisions and immune escape, thereby providing pathways for intercepting or treating metastasis. New molecular insights provide preliminary evidence that these behaviors are receptor-intrinsic, with each isoform signaling through distinct effectors to differentially engage downstream signaling networks associated with either ‘go’ or ‘grow’ phenotypes. Moreover, we show that the ‘go’ phenotype found in p95 expressing cells is associated with upregulation of PDL1 immune checkpoint expression to allow for evasion of adaptive immunity. A strong scientific premise supports testing the central hypothesis that biased signaling of HER2 isoforms promotes functionally selective programs of cancer cell proliferation, invasion, and immune escape. Three specific aims are proposed to test this hypothesis. (Aim 1) Determine how functionally selective HER2 isoform signaling drives ‘grow’ or ‘go’ cell decisions, (Aim 2). Determine how p95 HER2 signaling promotes invasion and early dissemination. (Aim 3) Determine how HER2 isoforms drive intrinsic pathways for avoiding immune recognition. This approach is technically innovative and includes a MPI interdisciplinary team skilled in state-of-the-art live imaging, receptor engineering, and cancer immunology. The innovation of the proposal lies in the identification of isoform-induced signaling bias at HER2 that leads to functionally selective behaviors of tumor cells, including proliferation, motility, and immune escape. The expected long-term impact will be elucidation of signaling targets that could lead to strategies for preventing breast cancer metastasis. The mouse models that we describe in the research plan are utilized to recapitulate the extraordinary complexity of the in vivo environment (such as early dissemination to distant organs and immune escape), which cannot be modelled in vitro.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary Hypersensitivity to touch is common in neurodevelopmental disorders including autism spectrum disorder (ASD). Individuals with ASD can have aversive responses to certain textures or human touch, which can lead to emotional distress, social withdrawal, and difficulties accomplishing everyday tasks. In humans and rodents, aberrant touch sensitivity perinatally is predictive of ASD-linked traits later in life. The molecules and mechanisms underlying touch sensation are just being elucidated, and little is known about how they relate to ASD. Touch sensation begins with the activity of mechanically activated PIEZO2 channels that transduce forces into electrical signals. The overall objective of the proposed research is to investigate the role(s) of the Ca2+ sensing protein caldendrin in regulating PIEZO2, touch sensation, and neurodevelopmental processes controlling cognition/affective behaviors. Our project builds on our discovery that mice lacking caldendrin (Cabp1 KO) display tactile hypersensitivity and increased activity of PIEZO2 in dorsal root ganglion neurons (DRGNs). Neurite outgrowth, which depends on PIEZO2 as well as Cav1 L-type Ca2+ channels, is abnormal in Cabp1 KO DRGNs and differs in cultures from males and females. Moreover, Cabp1 KO mice exhibit ASD-like phenotypes, such as anxiety and anti-social behavior, which are more severe in males than females. Considering that genetic silencing of some ASD-related genes in DRGNs of neonatal mice causes tactile hypersensitivity and ASD-linked behaviors in adulthood, our central hypothesis is that caldendrin modulates PIEZO2, Cav1, and the structural maturation of DRGNs early in development, which has sex-specific effects in driving synaptic plasticity in the brain and cognitive, affective, and social behaviors in adulthood. We will use state of the art methods in biochemistry, electrophysiology, and optical imaging to test the following specific aims: (1) elucidate the mechanism whereby caldendrin modulates the activity of PIEZO2; (2) define the contributions of caldendrin to sex- specific patterns of neurite development; and (3) determine how loss of function of caldendrin leads to aberrant cognitive/affective behaviors.

Fundacao Calouste Gulbenkian

Portuguese foundation supporting art, charity, science, and education internationally.