A5054039111- Pancreatic function and diabetes
- Diabetes and associated disorders
- Metabolism, Diabetes, and Cancer
- Diabetes Treatment and Management
- Adipose Tissue and Metabolism
- Advanced biosensing and bioanalysis techniques
- Cancer Genomics and Diagnostics
- Cancer Cells and Metastasis
- Diabetes Management and Research
- HER2/EGFR in Cancer Research
- Immune Cell Function and Interaction
- Molecular Biology Techniques and Applications
- CRISPR and Genetic Engineering
- Diet, Metabolism, and Disease
- Nanoparticle-Based Drug Delivery
- Receptor Mechanisms and Signaling
- Metabolomics and Mass Spectrometry Studies
- Cellular transport and secretion
- Endoplasmic Reticulum Stress and Disease
- Epigenetics and DNA Methylation
- Lung Cancer Treatments and Mutations
- Microtubule and mitosis dynamics
- Adenosine and Purinergic Signaling
- Immunotherapy and Immune Responses
- MicroRNA in disease regulation
Children's Hospital of Wisconsin
2024
Medical College of Wisconsin
2024
University of Michigan–Ann Arbor
2017-2022
University of Wisconsin–Madison
2011-2021
William S. Middleton Memorial Veterans Hospital
2015-2021
Diabetes Australia
2015
Madison Group (United States)
2015
Harvard University
2013
Immunomodulators that remodel the tumor immunosuppressive microenvironment have been combined with anti–programmed death 1 (α-PD1) or ligand (α-PDL1) immunotherapy but shown limited success in clinical trials. However, therapeutic strategies to modulate of lymph nodes largely overlooked. Here, we designed an albumin nanoparticle, Nano-PI, containing immunomodulators PI3Kγ inhibitor (IPI-549) and paclitaxel (PTX). We treated two breast cancer mouse models Nano-PI combination α-PD1, which...
BTBR mice develop severe diabetes in response to genetically induced obesity due a failure of the β-cells compensate for peripheral insulin resistance. In analyzing islet gene expression patterns, we observed that Pgter3, prostaglandin E receptor 3 (EP3), was upregulated with diabetes. The EP3 is stimulated by E2 (PGE2) and couples G-proteins Gi subfamily decrease intracellular cAMP, blunting glucose-stimulated secretion (GSIS). Also were several genes involved synthesis PGE2. We...
Triple-negative breast cancer (TNBC) has a high rate of metastasis, which is associated with stem-like cells (CSCs). Although Taxol (micelle formulation paclitaxel) the first line chemotherapy to treat TNBC, it increases CSCs in residual tumors. Abraxane, albumin nanoparticle paclitaxel, showed lower plasma concentration compared both human and animal models, but not clear why Abraxane superior efficacy treatment metastatic humans. In this study, we intend investigate if eliminates for its...
Aging is accompanied by impaired glucose homeostasis and an increased risk of type 2 diabetes, culminating in the failure insulin secretion from pancreatic β-cells. To investigate effects age on β-cell metabolism, we established a novel assay to directly image islet metabolism with NAD(P)H fluorescence lifetime imaging (FLIM). We determined that mitochondrial activity underlies age-dependent loss human islets. FLIM revealed comparable decline function islets aged mice (≥24 months), result...
Monocytes are immune regulators implicated in the pathogenesis of type 1 diabetes (T1D), an autoimmune disease that targets insulin-producing pancreatic β cells. We determined monocytes recent onset (RO) T1D patients and their healthy siblings express proinflammatory/cytolytic transcriptomes hypersecrete cytokines response to lipopolysaccharide exposure compared unrelated controls (uHCs). Flow cytometry measured elevated circulating abundances intermediate >2-fold more CD14 + CD16 HLADR...
We previously mapped a type 2 diabetes (T2D) locus on chromosome 16 (Chr 16) in an F2 intercross from the BTBR T (+) tf (BTBR) Lepob/ob and C57BL/6 (B6) mouse strains. Introgression of Chr into B6 mice resulted consomic with reduced fasting plasma insulin elevated glucose levels. derived panel sub-congenic narrowed susceptibility to 1.6 Mb region. this fragment lean (B6.16BT36–38) replicated phenotypes mice. Pancreatic islets B6.16BT36–38 were defective second phase secretion, suggesting...
Uncontrolled glycemia is a hallmark of diabetes mellitus and promotes morbidities like neuropathy, nephropathy, retinopathy. With the increasing prevalence diabetes, both immune-mediated type 1 obesity-linked 2, studies aimed at delineating pathophysiology therapeutic mechanisms are critical importance. The β-cells pancreatic islets Langerhans responsible for appropriately secreting insulin in response to elevated blood glucose concentrations. In addition other nutrients, also stimulated by...
Recently, a novel type 1 diabetes association locus was identified at human chromosome 6p31.3, and transcription factor 19 ( TCF19) is likely causal gene. Little known about Tcf19, we now show that it plays role in both proliferation apoptosis insulinoma cells. Tcf19 expressed mouse islets, with increasing mRNA expression nondiabetic obesity. The of correlated β-cell mass expansion, suggesting may be transcriptional regulator mass. Increasing decreasing apoptotic cell death are two...
One complication to comparing β-cell function among islet preparations, whether from genetically identical or diverse animals human organ donors, is the number of islets required per assay. Islet numbers can be limiting, meaning that fewer conditions tested; other measurements must excluded; pooled multiple animals/donors for each experiment. Furthermore, pooling negates possibility performing single-islet comparisons. Our aim was validate a 96-well plate-based single insulin secretion assay...
The α-subunit of the heterotrimeric Gz protein, Gαz, promotes β-cell death and inhibits replication when pancreatic islets are challenged by stressors. Thus, we hypothesized that loss Gαz protein would preserve functional mass in nonobese diabetic (NOD) model, protecting from overt diabetes. We saw protection diabetes was robust durable up to 35 weeks age knockout mice. By 17 age, Gαz-null NOD mice had significantly higher diabetes-free survival than wild-type littermates. Islets these...
Elevated islet production of prostaglandin E2 (PGE2), an arachidonic acid metabolite, and expression receptor subtype EP3 (EP3) are well-known contributors to the β-cell dysfunction type 2 diabetes (T2D). Yet, many same pathophysiological conditions exist in obesity, little is known about how PGE2 signaling pathway influences nondiabetic function. In this work, plasma metabolite levels were quantified a cohort T2D human subjects identify their relationship with glycemic control, systemic...
Uncontrolled glycemia is a hallmark of diabetes mellitus and promotes morbidities like neuropathy, nephropathy, retinopathy. With the increasing prevalence diabetes, both immune-mediated type 1 obesity-linked 2, studies aimed at delineating pathophysiology therapeutic mechanisms are critical importance. The β-cells pancreatic islets Langerhans responsible for appropriately secreting insulin in response to elevated blood glucose concentrations. In addition other nutrients, also stimulated by...
To explore T1D heterogeneity, the existence of endotypes, and their possible differential responses to immunotherapy administered at clinical onset, we studied 566 TrialNet trial participants (MMF-DZB, anti-CD20; GAD-alum; CTLA4-Ig; Canakinumab; ATG-GCSF). A bioassay, where participant serum is used induce transcription in healthy mononuclear cells, unsupervised cluster analyses were identify 2 major groups (Gp1 Gp2).Proportional subjects <18 years found Gp1 enriched with <14...
Abstract Objective Signaling through Prostaglandin E3 Receptor (EP3), a G protein-coupled receptor for E series prostaglandins such as prostaglandin 2 (PGE ), has been linked to the beta-cell dysfunction and loss of mass in type diabetes (T2D). In beta-cell, EP3 is specifically coupled unique cAMP-inhibitory protein, z . Divergent effects agonists antagonists or Gα on function, replication, survival depending whether islets are isolated from mice humans lean healthy, 1 diabetic, T2D state...
Abstract Triple-negative breast cancer (TNBC) represents about 20 percent of all cancers, with a poorer survival rate and being associated high-grade tumors the least favorable prognosis. Due to absence hormone receptors Her2 receptor, no targeted therapy is available chemotherapy standard treatment for TNBC patient. Paclitaxel widely used drug various cancers severe side effects due its solvent. Abraxane an albumin-bound nanoparticle paclitaxel less effects. Here we investigated whether...
Abstract Breast cancer stem cells (BCSCs) display plasticity allowing them to transition between quiescent mesenchymal- (M) and proliferative epithelial-like (E) states. This dynamic equilibrium of BCSCs in distinct M- E-like states coordinately drives tumorigenesis, metastasis treatment resistance. Despite the functional significance CSC tumor development progression, tracing BCSC state transitions under physiologic conditions is hampered by lack a dual fluorescent reporter monitor dynamics...
In type 1 diabetes (T1D), an autoimmune insulitis leads to β‐cell death. The non‐obese diabetic (NOD) mouse model mimics these facets of the human disease. Our laboratory has previously shown that mice deficient in alpha subunit heterotrimeric G protein, z (Gα ), were protected from developing chemically induced via decreased apoptosis and increased replication. We aimed confirm this NOD model, as well delineate mechanisms any protection. Between 4‐16 weeks age, weekly blood glucose levels...
Liberation of eicosapentaenoic acid (EPA) or arachidonic (AA) from membrane phospholipids is the first step in eicosanoid biosynthesis. Previously, we showed that production AA‐derived prostaglandin E2 (PGE2) and expression one PGE2 receptor, EP3, are both upregulated type 2 diabetic (T2D) islets contribute to beta‐cell dysfunction. We also restored function with an EP3 antagonist, suggesting as a T2D therapeutic target. In present study, explored different mechanism improve function:...
Type I Diabetes (TID) is fundamentally characterized by insulitis and islet inflammation which, ultimately, leads to β‐cell death. The non‐obese diabetic (NOD) mouse a well‐accepted model of TID as they exhibit insulitis, hyperglycemia ultimately failure. We have previously shown that loss the catalytic alpha subunit inhibitory heterotrimeric G‐protein, G z , Gα ameliorates streptozotocin (STZ)‐induced hyperglycemia, chemically‐induced TID. gone on confirm this protection in NOD delineate...
In the pancreatic islet, unique heterotrimeric G protein α‐subunit, Gα z , inhibits adenylate cyclase, reducing cyclic adenosine monophosphate (cAMP) levels. cAMP is an important potentiator of glucose‐stimulated insulin secretion (GSIS) and ‐null islets have enhanced GSIS. To further delineate mechanisms downstream that impact GSIS, exon array analysis was performed in isolated from 10‐week‐old male control mice. Candidate genes were flagged as being differentially expressed islets. test...
To better understand how T1D heterogeneity relates to disease progression and therapeutic responsiveness, we studied 566 recent onset subjects (mean age at onset: 16.5 +/- 8.2) that had participated in the following TrialNet trials: MMF-DZB, anti-CD20; GAD-alum; CTLA4-Ig; Canakinumab; ATG-GCSF. Our analysis began with a bioassay where plasma collected pre-intervention within 100 days of diagnosis was used induce transcription well-controlled peripheral blood mononuclear cell population....