Browsing by Author "Lin, Li"
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Item Characterization of lunar crust with moon mineralogy mapper data(2015-06-09) Sun, Ying; Lin, Li; Bird, Broxton; Johnson, Daniel; Licht, Kathy; Gilhooly, William P.This dissertation has three main focuses: (1) identify the distribution of a new rock type (Mg-spinel lithology) on the Moon and explore the likely petrogenesis of Mg-spinel; (2) investigate the presence of olivine in the crater central peaks and analyze the sources of olivine; (3) determine the compositional variations of lunar crust with depth, and establish a new model to describe the structure of the lunar crust.Item Combined loss of Tet1 and Tet2 promotes B-cell, but not myeloid malignancies in mice.(Elsevier, 2015-11-24) Zhao, Zhigang; Chen, Li; Dawlaty, Meelad M.; Pan, Feng; Weeks, Ophelia; Zhou, Yuan; Cao, Zeng; Shi, Hui; Wang, Jiapeng; Lin, Li; Chen, Shi; Yuan, Weiping; Qin, Zhaohui; Ni, Hongyu; Nimer, Stephen D.; Yang, Feng-Chun; Jaenisch, Rudolf; Jin, Peng; Xu, Mingjiang; Department of Pediatrics, IU School of MedicineTET1/2/3 are methylcytosine dioxygenases that regulate cytosine hydroxymethylation. Tet1/2 are abundantly expressed in HSC/HPCs and are implicated in hematological malignancies. Tet2-deletion in mice causes myeloid malignancies, while Tet1-null mice develop B-cell lymphoma after an extended period of latency. Interestingly, TET1/2 are often concomitantly downregulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/2 in HSC maintenance and development of hematological malignancies using Tet1/2 double knockout (DKO) mice. DKO and Tet2−/− HSC/HPCs showed overlapping and unique 5hmC and 5mC profiles, and behaved differently. DKO mice exhibited strikingly decreased incidence and delayed-onset of myeloid malignancies compared to Tet2−/− mice, and in contrast developed lethal B-cell malignancies. Transcriptome analysis of DKO tumors revealed expression changes in many genes dysregulated in human B-cell malignancies, such as LMO2, BCL6 and MYC. These results highlight the critical roles of TET1/2 individually and together via communication in the pathogenesis of hematological malignancies.Item Disease-associated astrocytes and microglia markers are upregulated in mice fed high fat diet(Springer Nature, 2023-08-09) Lin, Li; Basu, Rashmita; Chatterjee, Debolina; Templin, Andrew T.; Flak, Jonathan N.; Johnson, Travis S.; Pharmacology and Toxicology, School of MedicineHigh-fat diet (HFD) is associated with Alzheimer's disease (AD) and type 2 diabetes risk, which share features such as insulin resistance and amylin deposition. We examined gene expression associated with astrocytes and microglia since dysfunction of these cell types is implicated in AD pathogenesis. We hypothesize gene expression changes in disease-associated astrocytes (DAA), disease-associated microglia and human Alzheimer's microglia exist in diabetic and obese individuals before AD development. By analyzing bulk RNA-sequencing (RNA-seq) data generated from brains of mice fed HFD and humans with AD, 11 overlapping AD-associated differentially expressed genes were identified, including Kcnj2, C4b and Ddr1, which are upregulated in response to both HFD and AD. Analysis of single cell RNA-seq (scRNA-seq) data indicated C4b is astrocyte specific. Spatial transcriptomics (ST) revealed C4b colocalizes with Gfad, a known astrocyte marker, and the colocalization of C4b expressing cells with Gad2 expressing cells, i.e., GABAergic neurons, in mouse brain. There also exists a positive correlation between C4b and Gad2 expression in ST indicating a potential interaction between DAA and GABAergic neurons. These findings provide novel links between the pathogenesis of obesity, diabetes and AD and identify C4b as a potential early marker for AD in obese or diabetic individuals.Item RIPK1 and RIPK3 regulate TNFα-induced β-cell death in concert with caspase activity(Elsevier, 2022) Contreras, Christopher J.; Mukherjee, Noyonika; Branco, Renato C.S.; Lin, Li; Hogan, Meghan F.; Cai, Erica P.; Oberst, Andrew A.; Kahn, Steven E.; Templin, Andrew T.; Medicine, School of MedicineObjective: Type 1 diabetes (T1D) is characterized by autoimmune-associated β-cell loss, insulin insufficiency, and hyperglycemia. Although TNFα signaling is associated with β-cell loss and hyperglycemia in non-obese diabetic mice and human T1D, the molecular mechanisms of β-cell TNF receptor signaling have not been fully characterized. Based on work in other cell types, we hypothesized that receptor interacting protein kinase 1 (RIPK1) and receptor interacting protein kinase 3 (RIPK3) regulate TNFα-induced β-cell death in concert with caspase activity. Methods: We evaluated TNFα-induced cell death, caspase activity, and TNF receptor pathway molecule expression in immortalized NIT-1 and INS-1 β-cell lines and primary mouse islet cells in vitro. Our studies utilized genetic and small molecule approaches to alter RIPK1 and RIPK3 expression and caspase activity to interrogate mechanisms of TNFα-induced β-cell death. We used the β-cell toxin streptozotocin (STZ) to determine the susceptibility of Ripk3+/+ and Ripk3-/- mice to hyperglycemia in vivo. Results: Expression of TNF receptor signaling molecules including RIPK1 and RIPK3 was identified in NIT-1 and INS-1 β cells and isolated mouse islets at the mRNA and protein levels. TNFα treatment increased NIT-1 and INS-1 cell death and caspase activity after 24-48 h, and BV6, a small molecule inhibitor of inhibitor of apoptosis proteins (IAPs) amplified this TNFα-induced cell death. RIPK1 deficient NIT-1 cells were protected from TNFα- and BV6-induced cell death and caspase activation. Interestingly, small molecule inhibition of caspases with zVAD-fmk (zVAD) did not prevent TNFα-induced cell death in either NIT-1 or INS-1 cells. This caspase-independent cell death was increased by BV6 treatment and decreased in RIPK1 deficient NIT-1 cells. RIPK3 deficient NIT-1 cells and RIPK3 kinase inhibitor treated INS-1 cells were protected from TNFα+zVAD-induced cell death, whereas RIPK3 overexpression increased INS-1 cell death and promoted RIPK3 and MLKL interaction under TNFα+zVAD treatment. In mouse islet cells, BV6 or zVAD treatment promoted TNFα-induced cell death, and TNFα+zVAD-induced cell death was blocked by RIPK3 inhibition and in Ripk3-/- islet cells in vitro. Ripk3-/- mice were also protected from STZ-induced hyperglycemia and glucose intolerance in vivo. Conclusions: RIPK1 and RIPK3 regulate TNFα-induced β-cell death in concert with caspase activity in immortalized and primary islet β cells. TNF receptor signaling molecules such as RIPK1 and RIPK3 may represent novel therapeutic targets to promote β-cell survival and glucose homeostasis in T1D.Item RIPK3 promotes islet amyloid-induced β-cell loss and glucose intolerance in a humanized mouse model of type 2 diabetes(Elsevier, 2024) Mukherjee, Noyonika; Contreras, Christopher J.; Lin, Li; Colglazier, Kaitlyn A.; Mather, Egan G.; Kalwat, Michael A.; Esser, Nathalie; Kahn, Steven E.; Templin, Andrew T.; Biochemistry and Molecular Biology, School of MedicineObjective: Aggregation of human islet amyloid polypeptide (hIAPP), a β-cell secretory product, leads to islet amyloid deposition, islet inflammation and β-cell loss in type 2 diabetes (T2D), but the mechanisms that underlie this process are incompletely understood. Receptor interacting protein kinase 3 (RIPK3) is a pro-death signaling molecule that has recently been implicated in amyloid-associated brain pathology and β-cell cytotoxicity. Here, we evaluated the role of RIPK3 in amyloid-induced β-cell loss using a humanized mouse model of T2D that expresses hIAPP and is prone to islet amyloid formation. Methods: We quantified amyloid deposition, cell death and caspase 3/7 activity in islets isolated from WT, Ripk3-/-, hIAPP and hIAPP; Ripk3-/- mice in real time, and evaluated hIAPP-stimulated inflammation in WT and Ripk3-/- bone marrow derived macrophages (BMDMs) in vitro. We also characterized the role of RIPK3 in glucose stimulated insulin secretion (GSIS) in vitro and in vivo. Finally, we examined the role of RIPK3 in high fat diet (HFD)-induced islet amyloid deposition, β-cell loss and glucose homeostasis in vivo. Results: We found that amyloid-prone hIAPP mouse islets exhibited increased cell death and caspase 3/7 activity compared to amyloid-free WT islets in vitro, and this was associated with increased RIPK3 expression. hIAPP; Ripk3-/- islets were protected from amyloid-induced cell death compared to hIAPP islets in vitro, although amyloid deposition and caspase 3/7 activity were not different between genotypes. We observed that macrophages are a source of Ripk3 expression in isolated islets, and that Ripk3-/- BMDMs were protected from hIAPP-stimulated inflammatory gene expression (Tnf, Il1b, Nos2). Following 52 weeks of HFD feeding, islet amyloid-prone hIAPP mice exhibited impaired glucose tolerance and decreased β-cell area compared to WT mice in vivo, whereas hIAPP; Ripk3-/- mice were protected from these impairments. Conclusions: In conclusion, loss of RIPK3 protects from amyloid-induced inflammation and islet cell death in vitro and amyloid-induced β-cell loss and glucose intolerance in vivo. We propose that therapies targeting RIPK3 may reduce islet inflammation and β-cell loss and improve glucose homeostasis in the pathogenesis of T2D.Item Ten-eleven translocation protein 1 modulates medulloblastoma progression(BMC, 2021-04-29) Kim, Hyerim; Kang, Yunhee; Li, Yujing; Chen, Li; Lin, Li; Johnson, Nicholas D.; Zhu, Dan; Robinson, M. Hope; McSwain, Leon; Barwick, Benjamin G.; Yuan, Xianrui; Liao, Xinbin; Zhao, Jie; Zhang, Zhiping; Shu, Qiang; Chen, Jianjun; Allen, Emily G.; Kenney, Anna M.; Castellino, Robert C.; Van Meir, Erwin G.; Conneely, Karen N.; Vertino, Paula M.; Jin, Peng; Li, Jian; Biostatistics, School of Public HealthBackground: Medulloblastoma (MB) is the most common malignant pediatric brain tumor that originates in the cerebellum and brainstem. Frequent somatic mutations and deregulated expression of epigenetic regulators in MB highlight the substantial role of epigenetic alterations. 5-hydroxymethylcytosine (5hmC) is a highly abundant cytosine modification in the developing cerebellum and is regulated by ten-eleven translocation (TET) enzymes. Results: We investigate the alterations of 5hmC and TET enzymes in MB and their significance to cerebellar cancer formation. We show total abundance of 5hmC is reduced in MB, but identify significant enrichment of MB-specific 5hmC marks at regulatory regions of genes implicated in stem-like properties and Nanog-binding motifs. While TET1 and TET2 levels are high in MBs, only knockout of Tet1 in the smoothened (SmoA1) mouse model attenuates uncontrolled proliferation, leading to a favorable prognosis. The pharmacological Tet1 inhibition reduces cell viability and platelet-derived growth factor signaling pathway-associated genes. Conclusions: These results together suggest a potential key role of 5hmC and indicate an oncogenic nature for TET1 in MB tumorigenesis, suggesting it as a potential therapeutic target for MBs.Item Understanding Treatment Burden and Quality of Life Impact of Participating in an Early-Phase Pediatric Oncology Clinical Trial: A Pilot Study(Sage, 2018-01) Crane, Stacey; Backus, Lori; Stockman, Beth; Carpenter, Janet S.; Lin, Li; Haase, Joan E.; School of NursingPURPOSE: Early-phase clinical trials (EPTs) have led to new, more effective treatment options for children with cancer. Despite the extensive use of EPTs in pediatric oncology, little is known about parent and child experiences during EPT participation. The purposes of this pilot study were to assess the feasibility and preliminary results of having children with cancer and their parents complete measures of treatment burden and quality of life (QOL) concurrent with EPT participation. METHODS: In this descriptive, longitudinal, pilot study, parents and children were followed for the first 60 days of an EPT. Feasibility was assessed by participant enrollment and retention and completion of measures. Measures completed included the following: demographic form (completed at baseline); Diary of Trial Experiences to capture treatment burden (completed ongoing); and PedsQL™ Quality of Life Inventories, Cancer Modules, and Family Impact Module (completed at baseline, post-first disease evaluation, and off-study). Data were analyzed using descriptive statistics. RESULTS: Feasibility goals of enrollment, retention, and measure completion were partially met. Preliminary treatment burden and QOL results are provided. CONCLUSIONS: While QOL assessments may provide insight into EPT experiences, future studies need to be conducted at multiple sites and enrollment goals must account for participant attrition.Item USING AIRBORNE HYPERSPECTRAL IMAGERY TO ESTIMATE CHLOROPHYLL A AND PHYCOCYANIN IN THREE CENTRAL INDIANA MESOTROPHIC TO EUTROPHIC RESERVOIRS(2007-08-08T15:35:17Z) Sengpiel, Rebecca Elizabeth; Lin, Li; Tedesco, Lenore P.; Wilson, Jeffrey S. (Jeffrey Scott), 1967-This thesis presents the results of an analysis of predicting phytoplankton pigment concentrations (chlorophyll a and phycocyanin) from remotely sensed imagery. Hyperspectral airborne and hand-held reflectance spectra were acquired on three reservoirs (Geist, Morse and Eagle Creek) in Central Indiana, USA. Concurrent with the reflectance acquisition, in situ samples were collected and analyzed in laboratories to quantify the pigment concentration and other water quality parameters. The resultant concentration was then linked to Airborne Imaging Spectrometer for Applications (AISA) reflectance spectra for the sampling stations to develop predictive models. AISA reflectance spectra were extracted from the imagery which had been processed for radiometric calibration and geometric correction. Several previously published algorithms were examined for the estimation of pigment concentration from the spectra. High coefficients of determination were achieved for predicting chlorophyll a in two of the three reservoirs (Geist R2 = 0.712, Morse R2 = 0.895 and Eagle Creek Reservoir R2 = 0.392). This situation was similar for PC prediction, where two of the three reservoirs had high coefficients of determination between pigment concentration and reflectance (Geist R2 = 0.805, Morse R2 = 0.878 and Eagle Creek Reservoir R2 = 0.316). The results of this study show that reflectance spectra collected with an airborne hyperspectral imager are statistically significant, p < 0.03, in predicting chlorophyll a and phycocyanin pigment concentration in all three reservoirs in this study without the consideration of other parameters. The algorithms were then applied to the AISA image to generate high spatial resolution (1 m2) maps of Chlorophyll a and Phycocyanin distribution for each reservoir.Item β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances(MDPI, 2021-11-22) Mukherjee, Noyonika; Lin, Li; Contreras, Christopher J.; Templin, Andrew T.; Biochemistry and Molecular Biology, School of Medicineβ-cell death is regarded as a major event driving loss of insulin secretion and hyperglycemia in both type 1 and type 2 diabetes mellitus. In this review, we explore past, present, and potential future advances in our understanding of the mechanisms that promote β-cell death in diabetes, with a focus on the primary literature. We first review discoveries of insulin insufficiency, β-cell loss, and β-cell death in human diabetes. We discuss findings in humans and mouse models of diabetes related to autoimmune-associated β-cell loss and the roles of autoreactive T cells, B cells, and the β cell itself in this process. We review discoveries of the molecular mechanisms that underlie β-cell death-inducing stimuli, including proinflammatory cytokines, islet amyloid formation, ER stress, oxidative stress, glucotoxicity, and lipotoxicity. Finally, we explore recent perspectives on β-cell death in diabetes, including: (1) the role of the β cell in its own demise, (2) methods and terminology for identifying diverse mechanisms of β-cell death, and (3) whether non-canonical forms of β-cell death, such as regulated necrosis, contribute to islet inflammation and β-cell loss in diabetes. We believe new perspectives on the mechanisms of β-cell death in diabetes will provide a better understanding of this pathological process and may lead to new therapeutic strategies to protect β cells in the setting of diabetes.