Melinda Larsen - US grants
Affiliations: | Biology | State University of New York, Albany, Albany, NY, United States |
Area:
Molecular Biology, Cell Biology, Human DevelopmentWe are testing a new system for linking grants to scientists.
The funding information displayed below comes from the NIH Research Portfolio Online Reporting Tools and the NSF Award Database.The grant data on this page is limited to grants awarded in the United States and is thus partial. It can nonetheless be used to understand how funding patterns influence mentorship networks and vice-versa, which has deep implications on how research is done.
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High-probability grants
According to our matching algorithm, Melinda Larsen is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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2001 — 2003 | Larsen, Melinda | F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Ecm, Integrins, and Action in Salivary Morphogenesis @ U.S. Nat'L Inst/Dental/Craniofacial Res DESCRIPTION: (provided by applicant) Branching morphogenesis is a complex process that occurs during the development of the salivary gland, lung, kidney, prostate, and mammary gland. Using the salivary gland organ culture system, some molecules required for branching have been identified, including integrins, the extracellular matrix (ECM), and the actin cytoskeleton, but mechanisms remain unclear. The first step in branching is formation of clefts in the epithelial surface. Collagen III has been localized to clefts, indicating it may play a role in cleft formation. Integrins are heterodimeric molecules, which span the plasma membrane and mediate interaction of the ECM with the actin cytoskeleton and are, therefore, likely involved in coordinating cell movements and/or shape changes involved in branching morphogenesis. This proposal will address the role of integrins and actin cytoskeleton in submandibular gland development with three specific aims: 1) identify the role of collagen III in cleft formation, 2) define the actin rearrangements and regulators required for cleft formation, and 3) determine if there is an adhesion complex assembled at the sites of cleft formation. Understanding the composition and function of cell-matrix contacts in salivary branching morphogenesis will lead to further understanding of complex developmental processes and provide insights that may facilitate development of rational approaches for salivary gland regeneration in cancer and Sjogren?s syndrome patients. |
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2008 — 2017 | Larsen, Melinda | R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Engineering Functioning Salivary Glands Using Micropatterned Scaffolds @ State University of New York At Albany [unreadable] DESCRIPTION (provided by applicant): The goal of this application is to engineer a complex 3D artificial salivary gland using an innovative strategy combining adult salivary gland cells with a micropatterned artificial scaffold. The long-range goal of my research program is to facilitate translational research by engineering of an artificial salivary gland for use in human patients suffering from salivary hypofunction. Head and neck radiation therapy and Sjogren's syndrome both lead to decreased saliva production following irreversible salivary gland tissue damage. In these patients, lack of saliva production causes significant morbidity due to dry mouth that results in dysphasia, dental caries, oropharyngeal infections, mucositis, and loss of taste. A novel strategy for restoring salivary flow is to replace damaged salivary tissue with engineered tissue that is composed of self-organized cells attached to a scaffold. The hypothesis tested in this application is that self-organized salivary gland functional units that are attached to a micropatterned artificial scaffold can create a functioning artificial gland. This hypothesis is based on our previous demonstration that embryonic salivary gland cells have an inherent capacity to self- organize into functional salivary gland tissue. In Aim 1, conditions will be established for growing primary adult mouse salivary gland cells, a functionalized micropatterned scaffold will be created, and conditions whereby the salivary gland cells can attach to the scaffold will be established. In the second Aim, we will assemble an engineered gland by first facilitating self-organization of the adult salivary gland cells into functional units and then attach these units to the scaffold through functionalized nucleation sites, and form a 3D artificial gland structure. The function of this artificial gland will be tested in vivo in a future R01 application. The methods used for this approach will facilitate engineering of a human artificial salivary gland and also serve as a prototype for engineering other complex branched organs such as pancreas, kidney, and lung. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: The data obtained from this grant will advance basic scientific knowledge regarding the ability of adult salivary epithelial cells to self-organize into saliva-secreting structures when placed in a local environment consisting of the appropriate extracellular matrix composition and structure. We also create an artificial scaffold to which we can attach salivary gland cells and that will function as a conduit for delivery of saliva into the oral cavity. Together, the self-organized cells attached to the artificial scaffold will create an artificial salivary gland that will be tested for function in vivo in a future R01 application. This work will lead to a human artificial salivary gland will improve the oral, dental, and overall health of patients suffering from lack of saliva production by the salivary gland due to Sjogren's syndrome, radiation therapy, or other causes. [unreadable] [unreadable] [unreadable] |
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2008 | Hartmann, Dirk Larsen, Melinda |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Modeling Dynamics of Salivery Gland Branching Morphogenesis @ State University of New York At Albany [unreadable] DESCRIPTION (provided by applicant): This application is a collaborative project between an experimental biologist and a theoretical mathematician in order to develop a simulation framework to model the early stages of salivary gland branching morphogenesis and create an interactive tool that can be used to predict cell behavior within this context. Existing strategies for engineering salivary glands have been unable to create a complex branched structure or successfully produce saliva-secreting acinar cells, which may relate to the lack of appropriate 3D structure in these models. Although there is currently a clinical need for artificial salivary glands to replace the damaged saliva-producing tissue in patients suffering from Sj"gren's Syndrome or from side effects of radiation therapy for head and neck tumors, few predictive tools are available to model cell behavior. To engineer branched tissues, we need to understand how the branching occurs during development and how signaling pathways translate into physical changes. While many signaling pathways and structural components have been identified that play a role in branching, they so far have not been incorporated into a comprehensive integrated model that explains branching morphogenesis. This highly dynamic structural process can hardly be understood using conventional molecular biology methods alone. Only a close association between experiments and mathematical modeling will allow an integrated, systems level understanding of the process of branching morphogenesis. We previously generated a simulation framework to model lung branching based on localized proliferation. This model is limited since basement membrane dynamics are critical for branching. Our hypothesis is that basement membrane dynamics controlled by Rho kinase (ROCK)-mediated signaling is a critical component of salivary gland branching morphogenesis. To address this hypothesis and to create a framework for understanding the role of basement membrane dynamics during branching morphogenesis, we propose five specific aims: Specific Aim 1 Develop a simulation framework for salivary gland branching morphogenesis based on Level Set Methods, Specific Aim 2 Develop the experimental model system and compare experimental results with predictions of the new mathematical model and simulation framework, Specific Aim 3 Investigate the function of cytoskeletal inhibitors on branching morphogenesis and use this data to train the model, Specific Aim 4 Determine if ROCK inhibitors affect cytoskeletal tension during branching morphogenesis, and Specific Aim 5 Identify the cellular mechanism by which ROCK affects branching morphogenesis. The robust simulation framework and the mathematical models developed as a result of this project will constitute the first crucial step towards development of a comprehensive model of salivary gland branching morphogenesis. Significantly, it will guide experimentalists by revealing missing links and suggesting directions for future research. Further, the mathematical model and simulation framework can be modified as more data is obtained and will provide us with a tool to predict, and eventually, control cell behavior on different matrix substrates for intelligent engineering of a functional salivary gland. Project Narrative: The data obtained from this grant will advance basic scientific knowledge regarding the role of the basement membrane in control of branching morphogenesis in the salivary gland. In addition, we will create a mathematical model that incorporates experimental analysis of both biochemical and physical control. The model will be implemented in an appropriate numerical framework. This software tool will be accessible by a front end user-friendly interface, such that it will be available for other experimental biologists to use as a research tool for testing hypothesis in silico before experimenting with live tissue. Finally, in generating this model that allows us to describe and predict cell behavior within this context, we will gain insights into new methods for controlling cells for engineering of tissues which require prediction of cell behavior. This work will lead to generation of new models for tissue engineering. [unreadable] [unreadable] [unreadable] |
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2009 — 2010 | Larsen, Melinda | RC1Activity Code Description: NIH Challenge Grants in Health and Science Research |
A High-Resolution in Situ Proteomics Atlas of Salivary Gland Development @ State University of New York At Albany DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (06) Enabling Technologies and specific Challenge Topic, 06-DE-102 Structural and Molecular Atlases of Craniofacial Development. A critical issue for understanding organ development at a systems level is knowledge of temporal and spatial patterns of gene and protein expression throughout development. We have developed a novel fluorescence-based multiplexing technology for simultaneously tracking dozens of proteins within single formalin-fixed, paraffin-embedded tissue sections and novel software algorithms for quantifying and categorizing protein localization patterns for these markers at the subcellular level. This method involves direct immunohistochemistry (IHC) and automated imaging followed by complete inactivation of fluorophores that are directly conjugated to antibody probes. This direct IHC approach allows sequential multiplexed probing of the same tissue with multiple antibodies to dramatically increase the number of markers that can be simultaneously visualized in a single sample when compared with classical indirect IHC. This method eliminates the need for multiple spectrally compatible fluorophores and for serial tissue sections, thus allowing large amounts of data to be generated from a small amount of material. The dye-inactivation multiplexing procedure has been thoroughly characterized and tested through 100 rounds of cycling with no loss in tissue morphology or antigenicity. In this project, we will apply this innovative multiplexing technology for the first time to a developmental system to profile expression patterns of signaling proteins during mouse submandibular and sublingual salivary gland morphogenesis and differentiation in a developmental salivary gland tissue array. The end product will include a high- resolution in situ proteomics-based atlas, which categorizes and quantifies active signaling protein expression levels within specific cell types and subcellular compartments, throughout all key developmental time-points. This high-resolution anatomical systems-level analysis would be impossible to create using traditional genomics methods, which are done at the level of mRNA, or by traditional proteomic methods, which destroy the tissue context. This data set will complement the gene expression atlases developed through the intramural NIDCR program (Salivary Gland Atlas project, Drs. K. Yamada and M. Hoffman) and will integrate with other databases in FaceBase, and provide a truly unique data component for systems biology. The morphogenesis-related dataset will also inform a mathematical model of the developing salivary gland, (RO1DE0192444-01, M. Larsen,) and the differentiation-related dataset will identify new differentiation markers and pathway components for intelligent engineering of an artificial salivary gland (R21DE0192444-01, M. Larsen). This study will provide a foundation of basic developmental biology knowledge needed to interpret future studies in other normal and diseased mouse and human craniofacial tissues. Finally, the proposed studies will facilitate economic recovery through direct materials costs (i.e. microscope, fluidics, computers and controllers, and antibodies and supplies, which will all purchased from US vendors) and by providing two new positions to complete the antibody labeling and to become a key operator in Dr. Larsen's lab so that the technology can be applied to her future studies. The technology being applied to the atlas;however, is not currently commercially available to the public research community, but this project will facilitate the adaptation and transition of this powerful multiplexing method to mainstream research applications. The proposed studies will create an atlas of protein expression patterns in developing salivary gland using novel high-content methods. These methods allow multiple markers to be examined in the same sample, allowing true co-localization of multiple proteins through developmental stages. These studies will provide insight into the fundamental signaling events occurring during the process of salivary gland development and differentiation. |
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2009 — 2012 | Larsen, Melinda Yener, Bulent (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Modeling Dynamics of Salivary Gland Branching Morphogenesis @ State University of New York At Albany DESCRIPTION (provided by applicant): This application is a collaborative project between an experimental biologist and a theoretical mathematician in order to develop a simulation framework to model the early stages of salivary gland branching morphogenesis and create an interactive tool that can be used to predict cell behavior within this context. Existing strategies for engineering salivary glands have been unable to create a complex branched structure or successfully produce saliva-secreting acinar cells, which may relate to the lack of appropriate 3D structure in these models. Although there is currently a clinical need for artificial salivary glands to replace the damaged saliva-producing tissue in patients suffering from Sjgren's Syndrome or from side effects of radiation therapy for head and neck tumors, few predictive tools are available to model cell behavior. To engineer branched tissues, we need to understand how the branching occurs during development and how signaling pathways translate into physical changes. While many signaling pathways and structural components have been identified that play a role in branching, they so far have not been incorporated into a comprehensive integrated model that explains branching morphogenesis. This highly dynamic structural process can hardly be understood using conventional molecular biology methods alone. Only a close association between experiments and mathematical modeling will allow an integrated, systems level understanding of the process of branching morphogenesis. We previously generated a simulation framework to model lung branching based on localized proliferation. This model is limited since basement membrane dynamics are critical for branching. Our hypothesis is that basement membrane dynamics controlled by Rho kinase (ROCK)-mediated signaling is a critical component of salivary gland branching morphogenesis. To address this hypothesis and to create a framework for understanding the role of basement membrane dynamics during branching morphogenesis, we propose five specific aims: Specific Aim 1 Develop a simulation framework for salivary gland branching morphogenesis based on Level Set Methods, Specific Aim 2 Develop the experimental model system and compare experimental results with predictions of the new mathematical model and simulation framework, Specific Aim 3 Investigate the function of cytoskeletal inhibitors on branching morphogenesis and use this data to train the model, Specific Aim 4 Determine if ROCK inhibitors affect cytoskeletal tension during branching morphogenesis, and Specific Aim 5 Identify the cellular mechanism by which ROCK affects branching morphogenesis. The robust simulation framework and the mathematical models developed as a result of this project will constitute the first crucial step towards development of a comprehensive model of salivary gland branching morphogenesis. Significantly, it will guide experimentalists by revealing missing links and suggesting directions for future research. Further, the mathematical model and simulation framework can be modified as more data is obtained and will provide us with a tool to predict, and eventually, control cell behavior on different matrix substrates for intelligent engineering of a functional salivary gland. Project Narrative: The data obtained from this grant will advance basic scientific knowledge regarding the role of the basement membrane in control of branching morphogenesis in the salivary gland. In addition, we will create a mathematical model that incorporates experimental analysis of both biochemical and physical control. The model will be implemented in an appropriate numerical framework. This software tool will be accessible by a front end user-friendly interface, such that it will be available for other experimental biologists to use as a research tool for testing hypothesis in silico before experimenting with live tissue. Finally, in generating this model that allows us to describe and predict cell behavior within this context, we will gain insights into new methods for controlling cells for engineering of tissues which require prediction of cell behavior. This work will lead to generation of new models for tissue engineering. |
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2012 — 2016 | Castracane, James (co-PI) [⬀] Larsen, Melinda |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Engineering Functional Salivary Glands Using Micropatterned Scaffolds @ State University of New York At Albany DESCRIPTION (provided by applicant): Millions of people suffer from xerostomia, or dry mouth resulting from lack of saliva, causing a decreased quality of life resulting from multiple symptoms, including increased dental caries, oropharyngeal infections, difficulties with swallowing (dysphagia) and digestion (mucositis), loss of taste, and pain. As current treatments for these problems are inadequate (1), there is considerable interest in creating an artificial salivary gland. Maintenance of salivary acinar cell differentiation and function in vitro is criticl to the successful engineering of such constructs; however, this breakthrough has not yet been achieved. This is primarily due to the current lack of basic scientific knowledge regarding the specific extracellular signals that are required to maintain or induce acinar cell differentiation, which remains a substantial limitation in the ability to engineer a functional artificial salivary gland. An in vitro assay system is needed to identify required extracellular signals. We hypothesize that the combination of chemically-modified nanofibers presented to cells via microscale patterning in a 3D scaffold will support salivary acinar cell function. This application proposes an innovative, interdisciplinary strategy to create a high-throughput, non-invasive assay system that will be used to sense salivary acinar cell secretory function in live cells grown on scaffold materials, which has not been previously possible. A MEMS-based saliva sensor will be produced to accurately measure the concentration of a salivary secretory protein secreted by cells grown on unique scaffold combinations. A novel multiplexed immunocytochemistry method will be used to assess the extent of differentiation in fixed cells following the biosensor assay. Using an innovative combination of methods, nanotopography, micropatterning, and chemical signaling will be independently modulated, such that specific combinations of parameters will be identified that support acinar cell function. Scaffolds will be assessed for their ability to maintin acinar differentiation or promote re-differentiation using a combination of primary cells and cell lines. We will address this hypothesis in four specific aims: Aim 1: Develop a high-throughput MEMS probe array assay system to evaluate acinar cell function in vitro. Aim 2: Identify the ideal nanofiber configuration to support salivary acinar cell differentiation. Aim 3: Optimize nanofiber surface properties to enhance salivary gland acinar cell function. Aim 4: Identify an optimal microtopography to promote acinar cell function. The in vitro salivary gland construct produced in this application will be useful to identify pathways regulating acinar function and can be applied for drug screening. The principles developed as a result of this application will be applied in the future towards engineering of artificial glands designed to replicate salivary gland and other complex branching organs. |
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2012 — 2013 | Larsen, Melinda | R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Extracellular Scaffold Elasticity and Binding Sites in Acinar Differentiation @ State University of New York At Albany DESCRIPTION (provided by applicant): One of the most significant challenges currently facing the field of tissue engineering is the ability to stimulate and/or maintain epithelial cell differentiation in engineered tissues. Since epithelial cell secretory function is crucial to organ function, understanding the mechanisms regulating and maintaining cellular differentiation is critical to regenerating or engineering functional tissues. A man-made functional saliva-secreting salivary gland construct would greatly increase the quality of life for patients suffering from salivary hypofunction, but such engineered tissues have yet to be generated, and in vitro salivary acinar differentiation remains difficult to sustain. The cellular microenvironment plays a significant role in cell differentiation, and yet little is known regarding the specific characteristics of the microenvironment that regulate cell differentiation. Engineered scaffolds often fail to mimic the microenvironment and, in fact, the most effective scaffolds for tissue engineering are decellularized scaffolds derived from live tissue. Since the goal of tissue engineering is to be able to synthesize scaffolds that out-perform decellularized natural scaffolds, it is necessary to understand how the essential characteristics of the natural extracellular matrix (chemical, mechanical/elastic, and topological properties) affect cell differentiation. Recent studies have identified the importance of elasticity of the microenvironment in determining the extent of differentiation of mesenchymal stem cells; however, the significance of elasticity in regulation of epithelial tissue differentiation has not been investigated. Chemical signals, including growth regulatory factors and binding sites, have been much more extensively studied, but the relationship between chemical signals and elasticity remains largely unknown. The overall aim of this project is to define the function of substrate elasticity and cell binding site density in regulating submandibular salivary gland (SMG) acinar cell differentiation. We will use cell lines and embryonic primary cells to address this aim using novel tunable PEG hydrogel scaffolds. We hypothesize that acinar cell differentiation requires a compliant extracellular matrix having optimal cell binding sites which is disrupted at atypical substrate rigidities. To address this hypothesis, we propose to use tunable polyethylene-glycol (PEG)-based hydrogels in three specific aims: Aim 1. Develop PEG-based hydrogels of varied elasticity containing different levels of binding sites. Aim 2. Identify the contributions of elasticity and cell organization in modulating acinar cell differentiation using the hydrogel scaffolds. Aim 3. Use bilayer lithography to create microwell scaffolds for use with primary cells. Abbreviations: AFM, atomic force microscopy; Col IV, collagen type IV; ECM, extracellular matrix; GFP, green fluorescent protein; IKVAV, Isoleucine-Lysine-Valine-Alanine-Valine; PEG, poly(ethylene glycol); PCR, polymerase chain reaction; PEG-DMA, PEG-dimethylacrylate; PEG-TMA, PEG-trimethylacrylate; OMMA, oxiran-2-ylmethyl methacrylate; POMO, 2-((prop-2-ynyloxy)methyl)oxirane; SMG, submandibular salivary gland; transepithelial resistance, TER PUBLIC HEALTH RELEVANCE: This project will identify the necessary elastic and cell binding characteristics of a cellular scaffold to promote acinar differentiation. These results will provide a framework for future identification of other factors that influence acinar generation in a future proposal. These studies will eventually make possible the engineering of an artificial scaffold to alleviate symptoms in patients suffering from Sjogren's syndrome and other causes of salivary hypofunction, or dry mouth. |
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2018 — 2019 | Larsen, Melinda | R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Endothelial Cell Signaling in Regeneration @ State University of New York At Albany ABSTRACT Hyposalivation, which leads to ?dry mouth? and complications thereof, is a debilitating effect of Sjogren's Syndrome and occurs as a side-effect of radiation treatment for head and neck cancers. Significant alterations in the vasculature correlate with salivary hypofunction. Microvessel density is decreased in Sjogren's Syndrome and in irradiated glands, and aberrant vessels and premature arteriosclerosis are reported in Sjogren's Syndrome. Post-irradiation transplantation of bone marrow-derived and adipose-derived mesenchymal stem cells (MSCs) improves salivary flow and microvessel density. Additionally, transient delivery of FGF2 and VEGF after radiation damage restores microvessel density and salivary flow. Despite this evidence for restoration of vascular function as a treatment for salivary hypofunction, there are currently no therapies available to stimulate normal vessel structure and function in diseased salivary glands. The ability of combined therapies of endothelial cells (ECs) and MSCs to stimulate regeneration has not been directly tested. Further, the mechanisms through which ECs and MSCs restore salivary function remain unclear. Vasculature, which is comprised of ECs and pericyte support cells of mesenchymal origin, is known to perfuse tissues with nutrients. Additionally, ECs residing in capillaries are known to create vascular niches that stimulate regeneration in many organs through paracrine- and juxtacrine-acting factors that function as stem and progenitor cell-active trophogens. The profile of paracrine-acting factors produced by tissue-resident ECs is known to be organ-specific but remains uncharacterized in salivary glands. With this proposal we will address the following questions: 1) Can ECs stimulate salivary gland regeneration in vivo? 2) Is the ability of ECs to stimulate regeneration enhanced by MSCs? 3) What EC-dependent factors stimulate salivary gland regeneration? Here we investigate the hypothesis that salivary ECs secrete paracrine factors that stimulate functional salivary gland regeneration. To determine if EC +/- MSC transplantation enhances regeneration, in Aim 1 we will deliver EC +/- MSCs via hydrogels into a salivary gland resection model and examine gland regeneration at a cellular level and gland function by measuring salivary flow. The matrix metalloproteinase-degradable poly(ethylene glycol) (PEG)-based hydrogels have been used to successfully deliver MSCs into bone defect models in vivo. To identify paracrine-acting factors produced by ECs that could be used therapeutically, in Aim 2 we will use next generation RNA sequencing (RNA seq) to identify potential EC-dependent therapeutic factors and validate them in co-culture assays. This study will establish a new research team who will deliver proof of concept data for EC/MSC-dependent regeneration strategies. This study will enable future exploration of mechanisms through which ECs and EC-dependent paracrine factors stimulate salivary gland regeneration and facilitate future testing of these newly identified factors in salivary gland disease models for therapeutic benefit. Abbreviations: BM (bone marrow), DAPI (4',6-diamidino-2-phenylindole), EC (endothelial cell), FACS (fluorescent activated cell sorting), FGF2 (Fibroblast growth factor 2), FP (fluorescent protein), G-CSF (granulocyte colony-stimulating factor), IHC (immunohistochemistry), K (cytokeratin), MACS (magnetic bead activated cell sorting), MSC (mesenchymal stem cell), Mx-IHC (multiplexed immunohistochemistry), PEG (poly(ethylene glycol)), next generation RNA sequencing (RNA Seq), smooth muscle (SM), SMG (submandibular gland), SS (Sjogren's Syndrome), SCF(stem cell factor), VEGF164 (vascular endothelial growth factor, 164 aa) |
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2020 | Larsen, Melinda | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Nanofiber Scaffolds For Salivary Gland Regeneration @ State University of New York At Albany ABSTRACT Although extracellular matrix (ECM) remodeling is a natural response to injury, excessive ECM deposition, or fibrosis, limits regeneration, is a causative factor in hundreds of diseases, and leads to 40% of all deaths worldwide. Fibrosis occurs in salivary glands (SG) of patients treated with radiation for head and neck cancers and in patients suffering from the autoimmune disease, Sjögren?s Syndrome (SS). Despite the known inhibitory effects of fibrosis on tissue regeneration, and involvement of fibrosis in disease, the mechanisms through which fibrosis develops in the salivary gland and leads to dysfunction have not been explored. The stroma of salivary glands and other organs includes tissue-resident mesenchymal stem cells (MSCs). MSCs have inherent anti-fibrotic and anti-inflammatory functions; however, in disease states tissue- resident MSCs can undergo conversion into myofibroblasts (myo-FBs) and contribute to fibrosis. Therapeutic transplantation of MSCs has been used to treat many inflammatory disorders, with the most common tissue source for therapeutic MSCs being bone marrow (BM). Injection of BM-MSCs into non-obese diabetic (NOD) mice, a commonly used mouse model for SS, showed decreased inflammation and some limited SG functional restoration; however, effects were transient and the mechanisms leading to restored function remain unknown. Therapies that manipulate endogenous or apply exogenous MSCs hold clinical promise for diseases involving fibrosis and salivary hypofunction. Mechanisms through which tissue-resident MSCs and transplanted MSCs become fibrosis-generating myo-FBs in the SG are unknown; however, in many tissues signaling by Gli1 is required. We hypothesize that tissue-resident MSCs that undergo conversion to myo-FBs leading to fibrotic connective tissue exacerbating autoimmune disease and salivary dysfunction. The objective of this proposal is to determine if modulation of tissue-resident MSCs can limit fibrosis, inflammation, and restore gland function in injured and diseased salivary glands. We will address several important clinically relevant questions in this proposal: 1) Does Gli1 signaling contribute to fibrosis in injured/diseased salivary glands? 2) Can tissue- resident myo-FBs revert to a pro-regenerative MSC state and what are the associated genetic changes that demark this conversion? 3) In a murine Sjögren?s Syndrome model, will limiting conversion of tissue-resident MSCs into myo-FBs limit fibrosis, decrease disease progression, and facilitate functional restoration? The outcomes of our proposed study are expected to improve scientific knowledge by revealing cellular mechanisms through which MSCs contribute to fibrosis in SG. These findings will have a positive impact by identifying potential therapeutic targets. In addition, we will optimize scaffold delivery systems for MSCs and anti-fibrotic pharmacologicals for reducing fibrosis and restoring function in hypofunctioning salivary glands and other organs. |
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2021 — 2024 | Belfort, Marlene (co-PI) [⬀] Rodriguez, Havidan [⬀] Wagner, Christine Larsen, Melinda Wulfert, Edelgard (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Advance Adaptation: Project Sages: Striving to Achieve Gender Equity in Stem @ Suny At Albany The University at Albany is a doctoral institution with a strong commitment to research excellence. It boasts a highly diverse undergraduate population and strives to excel as a diverse and inclusive campus community; yet, women and women of color are underrepresented in the faculty ranks of STEM departments. The goal of Project SAGES is to create an environment in which women of all backgrounds and identities can thrive and develop their careers to their fullest potential. To accomplish this goal, Project SAGES seeks to increase the number of women scientists in STEM fields through proactive recruitment and unbiased hiring procedures and retain them by creating a climate and culture in which women feel supported, thrive, and advance in their careers from assistant to associate to full professor. |
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