1998 — 2002 |
Prossnitz, Eric R |
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. |
Mechanisms of Leukocyte Activation and Chemotaxis @ University of New Mexico
DESCRIPTION (Adapted from applicant's abstract): Leukocytes play an important role in host defense against invading microorganisms. Their ability to generate superoxide radicals and release degradative enzymes following migration to sites of inflammation is essential for this function. However, these same responses can also participate in the formation of numerous pathological conditions. The re-introduction of blood flow to ischaemic tissues following myocardial thrombosis, stroke or frostbite is responsible for the observed tissue damage, which can be alleviated by the depletion of neutrophils. Chemoattractants elicit their effects on neutrophils by binding to cell surface receptors coupled to guanine nucleotide-binding regulatory proteins (G proteins). The goal of this work is to understand the molecular mechanisms involved in the activation of leukocyte G protein-coupled chemoattractant receptors as they pertain to receptor signaling and processing, receptor interactions with the cytoskeleton and chemotaxis. The specific aims of this proposal include the determination of the role of the N-formyl peptide receptor (FPR) activation I the physical binding of the receptor to G protein. The proposed experiments will also determine residues responsible for the interaction of the receptor with the cytoskeleton and one of its major components, actin. We will generate mutations in the intracellular domains of the recombinant FPR and express these in tissue culture cell lines for functional analysis. The roles of specific residues, including potentially phosphorylated residues, will be determined with respect to receptor processing and chemotaxis utilizing a novel system we have recently developed. These complex activities likely require interactions following receptor phosphorylation. Utilizing this system, we will also examine the role(s) of the low MW G proteins rho, rac and cdc42 in leukocyte chemotaxis. Information obtained from the proposed studies is expected to extend our knowledge of the activation of signal transduction pathways by chemoattractant receptors with the long term goal that such knowledge will lead to the development of therapeutic means to control neutrophil activation and prevent the tissue damage resulting from the excessive activation of neutrophils following reperfusion.
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2004 — 2007 |
Prossnitz, Eric R |
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. |
Arrestin Activation Probed With Mass Spectrometry @ University of New Mexico
DESCRIPTION (provided by applicant): Arrestins interact with G protein-coupled receptors (GCPRs) and numerous downstream scaffolding and signaling molecules. These interactions promote the termination of signaling events initiated by activated GPCRs and result in GPCR internalization via calthrin-coated pits. Arrestins also associate with the Src-family kinases Src and Hck to initiate G protein-independent signaling pathways. Arrestins are therefore involved in virtually every aspect of normal and abnormal human physiology from the visual system via rhodopsin to the cardiovascular system via adrenergic receptors. Understanding arrestin activation mechanisms and the commensurate structural changes is essential to modulating a wide variety of disease states. Current models suggest that structural changes within arrestins are critical for proper function. The objectives of this application are to define these structural changes. To probe structural changes in arrestins during their functional cycle, we will use hydrogen exchange coupled with mass spectrometry (HX MS). By monitoring the mass changes that result from deuterium incorporation, HX MS can be used to probe protein structure and dynamics on a wide time-scale and with small quantities (pmol) of large (>40 kDa) proteins and protein complexes. The following specific aims will be accomplished: (1). We wilt probe the conformation of wild type arrestins in solution using HX MS and compare the results to similar HX MS studies of numerous mutant forms of arrestin that appear "pre-activated" and display higher affinity for GPCRs. (2). We will use HX MS to determine the structural alterations within arrestins following binding to the intracellular domains of GPCRs such as the N-formyl peptide receptor. (3). We will investigate binding-induced structural alterations during the interactions between arrestins and the Src-family kinase Hck, both with full-length Hck protein and the Hck SH3 domain which appears critical for binding. (4). We will design and examine the functional properties of novel site-directed mutants to test current structural/function hypotheses and newly acquired structural insights from the first three aims. By accomplishing these specific aims, we will definitively identify the structural changes that are involved in arrestin activation and those that accompany association with both upstream and downstream signaling partners. Our results will contribute to our basic knowledge of this key signaling molecule and provide the basis for the design of therapeutic agents related to GPCR signaling.
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2006 — 2010 |
Prossnitz, Eric R |
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. |
A Novel Intracellular 7tm Estrogen Receptor in Breast @ University of New Mexico
Estrogen is a crucial hormone in the human body, regulating many diverse physiological effects, including the growth, development and homeostasis of numerous tissues. Estrogen plays a critical role in the development of normal breast tissue, whereas responsiveness to estrogen represents one of the most important prognostic and therapeutic factors for patients with breast cancer. Many of these properties have been attributed to a soluble receptor for estrogen (ER) that functions in large part as a ligand-activated transcription factor. We have characterized a novel intracellular, 7-transmembrane spanning, G protein- coupled estrogen receptor (GPR30) that we propose functions alongside ER to regulate cell and tissue responsiveness to estrogen. We have discovered that GPR30 resides predominantly in the endoplasmic reticulum. The goal of Aim 1 is to determine the sequences within GPR30 that regulate its cellular location. We have also developed a novel family of fluorescent estrogen derivatives that binds to both the ER and GPR30. In Aim 2 we will use these fluorescent estrogens to develop cell-based estrogen binding assays for GPR30 and determine the binding specificities and affinities of a collection of estrogen-related compounds. Recently, we have characterized novel GPRSO-mediated signal transduction pathways in breast cancer cells. The nuclear accumulation of phosphatidylinositol 3,4,5-trisphosphate is initiated by estrogen-mediated transactivation of epidermal growth factor receptor (EGFR) by GPR30. The goal of Aim 3 is to investigate the mechanisms involved in EGFR transactivation with respect to EGFR phosphorylation and internalization, leading to transcriptional activation and cell growth control. Finally, we have established a colony of GPR30 null mice to dissect the in vivo function of GPR30 in breast growth and development. In Aim 4, we will characterize GPR30 expression in wild type mice and analyze the phenotypes of GPR30 null mice. We will also characterize the phenotypes of mice in which both GPR30 and the classical ERs have been deleted. With these tools, we can address estrogen-responsive signaling of GPR30 in a genetically defined background. The experiments proposed will be invaluable in defining the roles of this novel estrogen- responsive receptor in estrogen-mediated growth, proliferation, and differentiation in normal development as well as in neoplastic progression and the treatment of breast cancer.
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2007 — 2009 |
Prossnitz, Eric R |
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. |
The Role of Gpr30 in Advanced Endometrial Cancer @ University of New Mexico
Estrogen is a critical hormone in the human body because it regulates the growth, development and homeostasis of numerous tissues, including the regulation of mammalian reproduction and breast function, the central nervous and immune systems, skeletal physiology and vascular function. Our long-term goal is to elucidate the role of a novel intracellular, 7-transmembrane spanning, G protein-coupled estrogen receptor (GPR30) that we propose functions alongside the traditional estrogen receptor (ER) to regulate physiological responsiveness to estrogen. The specific hypothesis is that signaling through GPR30 regulates uterine function and cancer development. We base this hypothesis on our recent observations that 1) GPR30 represents a functional, estrogen-binding G protein-coupled receptor (GPCR), 2) GPR30 activates novel nuclear phosphatidylinositol signaling pathways and 3) GPR30 is specifically expressed in uterine glandular epithelium and overexpressed in endometrial cancer. The specific aims are: 1. Characterize estrogen-mediated cellular activation by GPR30. We will compare cellular signaling initiated by GPR30 and traditional ERs, stimulated by estrogen as well as estrogen analogs, and determine the effects of the clinically used kinase inhibitors Iressa and Lapatinib. 2. Animal models of GPR30 function in uterine biology and neoplasia. We will determine the developmental regulation of GPR30 in the normal and neoplastic mouse uterus. Using GPR30 knockout mice, we will determine the role of GPR30 in estrogen-dependent signaling in the uterus and how this regulates endometrial tumor development. 3. Evaluation of GPR30 expression in human endometrial cancer. We will investigate the role of GPR30 as a novel biomarker predictive of grade, stage and adverse outcome in intermediate and high-risk endometrial cancer. Characterizing the functions of this novel estrogen receptor in conjunction with translational clinical trials will contribute to our understanding of estrogen-induced growth and proliferation in the neoplastic uterus, leading to the development of GPR30 as a novel biomarker and as a target for diagnostic and therapeutic development.
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2008 — 2012 |
Prossnitz, Eric R |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Assay Implementation @ University of New Mexico Health Scis Ctr
Our Center now has a broad range of experience in developing cell and bead based assays for the flow cytometer As summarized in target team progress report. We have 13 laboratory trained senior staff including 9PhDs, 3 MSs, and 1 BS. Eleven of these staff have experience in AD/A with flow cytometry and 11 of these staff have experience in HTS robotics including 2 who have worked with chemical libraries. Since HT multiplexing by flow cytometry was introduced to the scientific community by our Center via MLSCN, our team members have supported outreach to develop a target pipeline that can extend indefinitely into the future. Sklar, Prossnitz, and Edwards have given >60 outreach presentations to highlight Roadmap targets and opportunities. Nearly all of the assays involve collaborations between the target provider and our Center. Among the assays submitted so far, essentially all but the VLA-4 and Quorom Sensing assays required a development phase.
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2008 — 2012 |
Arterburn, Jeffrey B (co-PI) [⬀] Oprea, Tudor I Prossnitz, Eric R |
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. |
Development of Gpr30-Selective Ligands @ University of New Mexico
DESCRIPTION (provided by applicant): Estrogen is a critical hormone in the human body that regulates the growth, development and homeostasis of many tissues. Physiological responses to estrogen include the regulation of mammalian reproduction and breast function, central nervous and immune systems, skeletal physiology and vascular function. We have recently described novel functions of the seven transmembrane G protein-coupled estrogen receptor, GPR30. This receptor is activated by both agonists and antagonists of the classical estrogen receptors, ER1 and ER2. Until recently there were no known specific ligands for GPR30, making traditional pharmacological approaches to the study of this receptor difficult. Our recent studies however have combined both virtual and biomolecular screening to discover the first GPR30-selective agonist, G-1. The specific aims of this application are: 1. Perform a combination of virtual and biomolecular screening to identify additional GPR30-specific ligands based on compounds presently known to bind and activate GPR30. Structure-activity analyses will be carried out to determine the critical molecular determinants for GPR30 binding selectivity and activity as compared to classical estrogen receptors. 2. Based on the biomolecular screening results and structure-activity analyses of Aim 1, rationally design and synthesize small libraries (up to 20 compounds per cycle) of novel G-1-based ligands. The goal of this aim is to separate agonism from antagonism within ligands, and to further evaluate the SAR of novel GPR30 ligands through targeted synthetic chemistry. 3. Characterize the biological functions of the compounds identified and synthesized in Aims 1 and 2. A collection of functional bioassays will be employed to characterize the biological effects of the compounds displaying activity. These assays will include intracellular signaling assays such as calcium mobilization, ERK and EGFR phosphorylation and PI3K activation;more complex cellular assays such as transcriptional activation, cell migration and proliferation;and in vivo studies using mouse models. Understanding the pharmacological profile and structure-activity relationships for ligand binding to GPR30 will be critical to the discovery of novel drugs that target this receptor for the purposes of revealing the underlying physiology of the receptor and developing therapeutic approaches for the improved treatment of estrogen-dependent cancers.
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2010 — 2014 |
Prossnitz, Eric R |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Womens Cancers Research Program @ University of New Mexico Health Scis Ctr
Affect; Animal Cancer Model; Animal Model; Apoptosis; Appointment; Area; Award; Basic Science; Behavior; Behavioral; Biology; biomarker; Breast; breast cancer registry; Cancer Center; Cancer Center Support Grant; Cancer Patient; Cancer Research Project; cancer therapy; Cell Communication; Cervical dysplasia; cheminformatics; Chemistry; Climate; Clinic; Clinical; Clinical Investigator; Clinical Research; Clinical Sciences; Clinical Trials; Collaborations; college; Communities; Community Outreach; Complement; Coupled; Critical Pathways; Critiques; Detection; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Discipline of obstetrics; Disease; Dissection; Early Diagnosis; Education and Outreach; effective intervention; Effectiveness; Endometrial; Endometrial Carcinoma; Endowment; Epidemiology; Epidermal Growth Factor Receptor; Epithelial; Estrogen Receptors; Etiology; Evaluation; Faculty; Family; Family member; Funding; Gene Expression Regulation; Genome Stability; Goals; Growth Factor; Growth Factor Receptors; GTP-Binding Proteins; Gynecologic Oncologist; Gynecology; Hispanics; Hormonal; Hormone Responsive; Hormones; Housing; Human Papilloma Virus Vaccine; Human Papillomavirus; human tissue; Image; imaging modality; Individual; inhibitor/antagonist; innovation; Institution; Instruction; Intervention Trial; Investigation; Iowa; Joints; Laboratories; Laboratory Research; Left; light scattering; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; malignant breast neoplasm; Malignant Female Reproductive System Neoplasm; Malignant neoplasm of cervix uteri; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Malignant Neoplasms; medical schools; meetings; member; Methods; minimally invasive; Minority; Mortality Vital Statistics; multidisciplinary; Native Americans; New Mexico; new technology; North Carolina; Not Hispanic or Latino; novel; oncology; Operative Surgical Procedures; Optics; outcome forecast; outreach program; Ovarian; Patients; Peer Review; Pharmacy facility; Phase; Population; population based; Population Sciences; preclinical study; Prevention; Principal Investigator; Productivity; prognostic; Program Development; programs; Prostate; Publications; Publishing; ranpirnase; Receptor Signaling; Recruitment Activity; Registries; repository; Research; Research Activity; Research Personnel; response; Role; Sampling; Scientist; Screening procedure; Seminal fluid; Services; Signal Pathway; Signal Transduction; Site Visit; small molecule; spectroscopic imaging; Spectrum Analysis; Speed (motion); Staging; Steroids; Strategic Planning; Stromal Cells; Suggestion; Surface; Techniques; Therapeutic; Therapy Clinical Trials; Time; trafficking; Training; Translating; Translational Research; translational study; Translations; tumor; United States National Institutes of Health; Universities; Urogenital Cancer; Visit; Woman; working group; Writing
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2011 — 2012 |
Prossnitz, Eric R |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Mlp Assay For Arrestin-Ap2 Inhibitors @ University of New Mexico Health Scis Ctr
DESCRIPTION (provided by applicant): G protein-coupled receptors (GPCR) play a critical role in almost every aspect of human physiology and disease. The protein arrestin plays a vital role in many of these pathways. Arrestin binds to the phosphorylated form of GPCRs and prevents the receptor from binding to and activating G proteins, resulting in desensitization. In addition, for many GPCRs, arrestin functions as an adapter molecule for internalization as well as secondary signaling. Arrestin mediates internalization via a domain that binds directly to clathrin and the adapter AP-2. Arrestins also bind to kinases and other signaling proteins. Our recent results have identified a specific molecular interaction between arrestin and AP-2 that is critical for the recycling certain GPCRs. We have also shown that disrupting this interaction induces a rapid apoptotic pathway for many GPCRs. To date there are no small molecules known that regulate interactions between arrestin and its interacting proteins. We have developed a high throughput flow cytometric assay involving AP-2 and a fluorescent arrestin peptide. The primary goal of the proposed research is to identify compounds that regulate the interaction between arrestin and AP-2, resulting in modulation of GPCR trafficking, signaling and apoptosis. A small molecule that inhibits this interaction will be a valuable tool to assess the role of AP-2 in the arrestin-dependent regulation of potentially hundreds of GPCRs and could represent the basis for therapeutic development through its ability to induce apoptosis in disease cells. PUBLIC HEALTH RELEVANCE: Receptors play a vital role in almost every aspect of human biology and disease. Receptor activity and function are mediated by a large collection of interacting proteins. The largest class of receptors is the G protein-coupled receptor (GPCR) family. The protein arrestin plays a critical role in both inhibiting and activating signaling by GPCRs. We have identified a specific interaction between arrestin and the cellular protein AP-2. To date there are no small molecules known that regulate interactions between arrestin and its interacting proteins. The goal of the proposed research is to identify compounds that inhibit or stimulate the interaction between arrestin and AP-2 to provide a valuable tool to assess the role of this interaction in the regulation of hundreds of GPCRs. Such a molecule would be of great benefit for researchers in the field and could find therapeutic utility in its ability to induce apoptosis in hyper stimulated disease cells such as cancer cells.
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2012 — 2021 |
Prossnitz, Eric R |
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. |
G Protein-Coupled Estrogen Receptor Gper and Breast Carcinogenesis @ University of New Mexico Health Scis Ctr
DESCRIPTION (provided by applicant): Estrogen and its receptors are critical factors in the development, progression, metastasis and treatment of breast cancer. In addition to the classical nuclear estrogen receptors, ERalpha and ERbeta, the 7-transmembrane G protein-coupled estrogen receptor GPER is now recognized as mediating many of the rapid signaling events associated with estrogen action. Anti-estrogen therapies in the form of selective estrogen receptor modulators (SERMs, such as tamoxifen) and selective estrogen receptor down regulators (SERDs, such as Fulvestrant) have been highly successful in many ER-positive breast cancer patients; however, intrinsic and acquired resistance remains significant problems. Tamoxifen and Fulvestrant are agonists of GPER, suggesting that GPER may play a role in resistance to these drugs. We have identified both a selective agonist and antagonists of GPER that will allow us to test the hypothesis that GPER plays an important role in breast carcinogenesis and treatment efficacy. Aim 1 will test whether GPER mediates cellular effects including proliferation, survival, transformation and migration in response to estrogen, anti-estrogens and GPER-selective ligands. Aim 2 will test whether selective targeting of GPER activity modulates carcinogenesis and metastasis in a murine model of breast cancer. Aim 3 will test whether selective activation and inhibition of GPER regulates proliferation and survival of cells in normal human breast tissue and human breast tumor explants. Significance: Completion of these aims will significantly advance our knowledge of and provide insight into the role of the novel estrogen receptor GPER in multiple aspects of breast cancer, from initiation to metastasis and drug resistance resulting in the identification of a novel therapeutic target for which highly selective antagonists exist. Further development of this antagonist could lead to a new drug for the treatment of GPER-expressing breast tumors.
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2016 — 2020 |
Arterburn, Jeffrey B (co-PI) [⬀] Prossnitz, Eric R |
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. |
Molecular Mechanisms and Applications of Novel Er/Gper-Selective Ligands @ University of New Mexico Health Scis Ctr
? DESCRIPTION (provided by applicant): Hormonal therapies have led to great improvements in the survival of women with estrogen receptor (ER)-positive breast cancers. However, residual tumor cells often become resistant to anti-estrogen treatment resulting in recurrences that are frequently more aggressive than the original cancer. Current ER- targeted hormonal therapies include selective estrogen receptor modulators (e.g. tamoxifen, raloxifene), pure antagonists (e.g. fulvestrant) and aromatase inhibitors, all of which can result in resistance following prolonged/chronic use. In addition, women taking SERMs also experience an increased incidence of endometrial thickening/hyperplasia, polyps and cancer. Multiple mechanisms have been described yielding these deleterious effects; however, most recently the 7-transmembrane spanning G protein-coupled receptor GPER has been demonstrated to contribute to both hormonal resistance and off-target effects in the uterus. This conclusion is supported by the fact that anti-estrogens act as agonists for GPER and that GPER activates growth factor receptor pathways that are important in hormonal resistance. In our previous work, we have discovered and characterized novel selective ligands for GPER that do not bind ER? or ER?. To date however, there are no known ligands that exhibit the inverse selectivity. Towards this overall goal, we have identified a family of novel small molecules that are highly selective for ER? and ER? vs. GPER. As estrogen and current anti-estrogens cannot distinguish between ER?/? and GPER, our newly identified small molecule provides the opportunity to create novel ligands and therapeutic agents to selectively manipulate and target classical ERs. Our hypothesis is that through selected chemical modifications to this first generation ER?/?-selective compound, we will optimize the overall affinity, receptor selectivity and agonist/antagonist profile with the ultimate goal of creating a truly ER?-selective antagonist. The specific aims of this proposal are 1. To design and synthesize a suite of derivatives based on our highly ER?/?-selective scaffold; 2. To evaluate and prioritize these compounds in vitro for receptor binding, cellular activation/inhibition of rapid and genomic pathways, cell proliferation and toxicity and 3. To determine the ability of compounds to modulate estrogen-dependent physiology in vivo, particularly the anti- tumor properties of lead compounds in mice bearing ER-dependent and anti-estrogen-resistant xenograft, orthotopic and PDX tumors. The successful completion of these aims should result in a better understanding of the ligand selectivity of ER?, ER? and GPER, the identification of innovative compounds that provide novel pharmacological tools for the study of estrogen biology and (patho)physiology, and, with their successful application in the clinic, reductions of the development of anti-estrogen resistant recurrences of breast cancer and off-target effects in the endometrium, ultimately enhancing survival and the quality of life of women with breast cancer.
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2017 — 2020 |
Prossnitz, Eric R |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Inflammation and Metabolism Core @ University of New Mexico Health Scis Ctr
SUMMARY The Inflammation and Metabolism Core (IMC) is focused on developing instrumentation and infrastructure that are required to enable advanced approaches to studies of metabolic and inflammatory functions at the University of New Mexico (UNM) Health Science Center (HSC). Inflammation and metabolism are multi- faceted and systemic networks. Their study requires measurements involving complex mixtures of cells from multiple organs and tissues using animal or human tissue. IMC will establish an integrated resource of expertise, cutting-edge equipment, and training to assess metabolic and inflammatory readouts within animal models and tissues. To support the goals and the aims of the Autophagy, Inflammation and Metabolism (AIM) in Disease Center of Biomedical Research Excellence (CoBRE), IMC will provide crucial new equipment for state-of-the-art assessment of inflammation and metabolism in whole animals. Furthermore, IMC will bring together disparate resources already existing at UNM HSC to enhance UNM investigator capability to study metabolism and inflammation. Each project that CoBRE mentored PIs (mPIs) propose requires metabolic or inflammatory assessment of unique animal models to perturb autophagy. IMC is essential to support these innovative studies. Experts in inflammation and metabolism will direct the core. IMC leadership will facilitate access to new and existing equipment. This centralization of resources and expertise will extend beyond CoBRE investigators and offer new opportunities and resources for investigators at UNM as well as in the region. IMC will support the following aims: Specific Aim 1. Create a centralized resource to assess inflammatory and metabolic dysfunction in animal models. Specific Aim 2. Support mPI research objectives and cultivate a new cohort of CoBRE investigators in their study of metabolic and inflammatory disorders. Specific Aim 3. Provide leadership to facilitate the increased utilization of metabolic and inflammatory measures as disease readouts.
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