Wound healing is an appropriate response to inflammation and tissue injury in the gastrointestinal tract. If wound healing responses are excessive, perpetuated, or prolonged, they lead to fibrosis, ...distortion of tissue architecture, and loss of function. This introductory editorial and the minireviews or reviews in this themes series highlight the diversity in severity and location of fibrosis in response to gastrointestinal inflammation. The multiplicity of cellular and molecular mediators and new players, including stem cells or extracellular matrix-producing cells derived from nonmesenchymal cell types, is reviewed. Comparisons of inflammation-induced fibrosis across organ systems and the need for integrated and systems-based molecular approaches, new imaging modalities, well-characterized animal models, cell culture models, and improved diagnostic or predictive markers are reviewed. To date, intestinal fibrosis has received much less attention than inflammation in terms of defining mechanisms and underlying causes. This themes series aims to illustrate the importance of research in this area in gastrointestinal health and disease.
PURPOSEThis analysis examined the role of a National Institutes of Health (NIH) individual Mentored Career Development Award (K01, K08, K23) on launching and sustaining independent research careers ...for early-career scientists, and investigated the effects of these awards during and after the doubling of the NIH budget.
METHODThe authors used grants data from the NIH covering the period 1990 through 2016, and compared success in receipt of R01 equivalent awards (R01 Eq.) and Research Project Grants (RPGs) for K awardees and K applicants who did not receive funding. The analysis combined regression discontinuity design with coarsened exact matching, and regression.
RESULTSOverall, receipt of K award was associated with a 24.1% increase in likelihood of first independent NIH award (P < .01), and a larger number of R01 Eq. and RPG awards. After accounting for first major independent awards, K awards were uncorrelated with receiving second major independent research awards. Comparing different funding periods, K01 awards were predictive of subsequent R01 Eq. and RPG awards after but not during the NIH doubling, K08 awards were predictive only during the NIH doubling, and K23 awards were predictive during both periods.
CONCLUSIONSReceipt of Mentored Career Development Awards was linked to increased likelihood that early-career scientists successfully transitioned to an independent research career. These findings indicate that extending funding to additional K award applicants with meritorious scores could significantly strengthen the pipeline of biomedical researchers. In addition, enhancing K awards may be relevant to sustaining research careers for clinician scientists.
ABSTRACT
Here, we use recent U.S. National Institutes of Health (NIH) data to document trends in the NIH‐funded workforce over time. Consistent with previous studies that were initiated by NIH, we ...find that the number of scientists funded on competing R01‐equivalent (R01 Eq.) and research project grants (RPGs) increased 2–5% per year between 2009 and 2016. Primary beneficiaries of this growth were experienced investigators (Exps), whereas the share of funding awarded to early‐stage investigators (ESIs) and new investigators (NIs) declined. The decline occurred even after NIH instituted the New and Early‐Stage Investigator policy in 2009. When we evaluate the investigator pool, we find that women and racial and ethnic minorities represent a higher percentage of NIs and ESIs relative to Exps. Thus, trends of diminishing support for NIs and ESIs may negatively impact the diversity of the current and future biomedical research workforce. We find some recent gains among women and Hispanics as part of the applicant and awardee pool for both R01 Eq. and RPGs, but significant, large gaps persist among nationally underrepresented racial minorities. Our findings suggest a need to prioritize investments and support of ESIs and NIs, groups in which women and racial and ethnic minorities represent a larger proportion of the applicant pool, to enhance diversity in the NIH‐funded workforce.—Nikaj, S., Roychowdhury, D., Lund, P. K., Matthews, M., Pearson, K. Examining trends in the diversity of the U.S. National Institutes of Health participating and funded workforce. FASEB J. 32, 6410–6422 (2018). www.fasebj.org
Gut microbiota play an important role in regulating the development of the host immune system, metabolic rate, and at times, disease pathogenesis. The factors and mechanisms that mediate interactions ...between microbiota and the intestinal epithelium are not fully understood. We provide novel evidence that microbiota may control intestinal epithelial stem cell (IESC) proliferation in part through microRNAs (miRNAs). We demonstrate that miRNA profiles differ dramatically across functionally distinct cell types of the mouse jejunal intestinal epithelium and that miRNAs respond to microbiota in a highly cell type-specific manner. Importantly, we also show that miRNAs in IESCs are more prominently regulated by microbiota compared with miRNAs in any other intestinal epithelial cell subtype. We identify miR-375 as one miRNA that is significantly suppressed by the presence of microbiota in IESCs. Using a novel method to knockdown gene and miRNA expression ex vivo enteroids, we demonstrate that we can knock down gene expression in Lgr5+ IESCs. Furthermore, when we knock down miR-375 in IESCs, we observe significantly increased proliferative capacity. Understanding the mechanisms by which microbiota regulate miRNA expression in IESCs and other intestinal epithelial cell subtypes will elucidate a critical molecular network that controls intestinal homeostasis and, given the heightened interest in miRNA-based therapies, may offer novel therapeutic strategies in the treatment of gastrointestinal diseases associated with altered IESC function.
Clinician–investigators, also called physician–scientists, offer critical knowledge and perspectives that benefit research on basic science mechanisms, improved diagnostic and therapeutic approaches, ...population and outcomes medicine, health policy, and health services, yet few clinically trained health professionals pursue a research career. Sustaining this workforce requires attention to the unique challenges faced by investigators who must achieve clinical and research competence during training and their careers. These challenges include the duration of required clinical training, limited or discontinuous research opportunities, high levels of educational debt, balancing the dual obligations and rewards of clinical care and research, competition for research funding, and the need for leadership development after training. Women and individuals from underrepresented racial and ethnic groups comprise a small percentage of this workforce.The authors summarize the recent literature on training for clinician–investigators, emphasizing approaches with encouraging outcomes that warrant broader implementation. Using this overview as background, they convened three workshops at the National Institutes of Health in 2016 to identify and refine key priorities for potential new pilot programs to recruit and retain the clinician–investigator workforce. From these workshops emerged three priorities for future pilot programs(1) support for research in residency, (2) new research on-ramps for health professionals at multiple career stages, and (3) national networks to diversify and sustain clinician–investigator faculty. Implementation of any pilot program will require coordinated commitment from academic health centers, medical licensing/certification boards, professional societies, and clinician–investigators themselves, in addition to support from the National Institutes of Health.
The National Institutes of Health (NIH) is committed to attracting, developing, and supporting the best scientists from all groups as an integral part of excellence in training. Biomedical research ...workforce diversity, capitalizing on the full spectrum of skills, talents, and viewpoints, is essential for solving complex human health challenges. Over the past few decades, the biomedical research workforce has benefited from NIH programs aimed at enhancing diversity. However, there is considerable room for improvement, particularly at the level of independent scientists and within scientific leadership. We provide a rationale and specific opportunities to develop and sustain a diverse biomedical research workforce through interventions that promote the successful transitions to different stages on the path toward completion of training and entry into the biomedical workforce.
MicroRNAs (miRNAs) have emerged as biomarkers of metabolic status, etiological factors in complex disease, and promising drug targets. Recent reports suggest that miRNAs are critical regulators of ...pathways underlying the pathophysiology of type 2 diabetes. In this study, we demonstrate by deep sequencing and real-time quantitative PCR that hepatic levels of Foxa2 mRNA and miR-29 are elevated in a mouse model of diet-induced insulin resistance. We also show that Foxa2 and miR-29 are significantly upregulated in the livers of Zucker diabetic fatty (fa/fa) rats and that the levels of both returned to normal upon treatment with the insulin-sensitizing agent pioglitazone. We present evidence that miR-29 expression in human hepatoma cells is controlled in part by FOXA2, which is known to play a critical role in hepatic energy homeostasis. Moreover, we demonstrate that miR-29 fine-tunes FOXA2-mediated activation of key lipid metabolism genes, including PPARGC1A, HMGCS2, and ABHD5. These results suggest that miR-29 is an important regulatory factor in normal metabolism and may represent a novel therapeutic target in type 2 diabetes and related metabolic syndromes.
Recent identification of intestinal epithelial stem cell (ISC) markers and development of ISC reporter mice permit visualization and isolation of regenerating ISCs after radiation to define their ...functional and molecular phenotypes. Previous studies in uninjured intestine of Sox9-EGFP reporter mice demonstrate that ISCs express low levels of Sox9-EGFP (Sox9-EGFP Low), whereas enteroendocrine cells (EEC) express high levels of Sox9-EGFP (Sox9-EGFP High). We hypothesized that Sox9-EGFP Low ISCs would expand after radiation, exhibit enhanced proliferative capacities, and adopt a distinct gene expression profile associated with rapid proliferation. Sox9-EGFP mice were given 14 Gy abdominal radiation and studied between days 3 and 9 postradiation. Radiation-induced changes in number, growth, and transcriptome of the different Sox9-EGFP cell populations were determined by histology, flow cytometry, in vitro culture assays, and microarray. Microarray confirmed that nonirradiated Sox9-EGFP Low cells are enriched for Lgr5 mRNA and mRNAs enriched in Lgr5-ISCs and identified additional putative ISC markers. Sox9-EGFP High cells were enriched for EEC markers, as well as Bmi1 and Hopx, which are putative markers of quiescent ISCs. Irradiation caused complete crypt loss, followed by expansion and hyperproliferation of Sox9-EGFP Low cells. From nonirradiated intestine, only Sox9-EGFP Low cells exhibited ISC characteristics of forming organoids in culture, whereas during regeneration both Sox9-EGFP Low and High cells formed organoids. Microarray demonstrated that regenerating Sox9-EGFP High cells exhibited transcriptomic changes linked to p53-signaling and ISC-like functions including DNA repair and reduced oxidative metabolism. These findings support a model in which Sox9-EGFP Low cells represent active ISCs, Sox9-EGFP High cells contain radiation-activatable cells with ISC characteristics, and both participate in crypt regeneration.
Ileocecal resection (ICR) is a commonly required surgical intervention in unmanageable Crohn's disease and necrotizing enterocolitis. However, the impact of ICR, and the concomitant doses of ...antibiotic routinely given with ICR, on the intestinal commensal microbiota has not been determined. In this study, wild-type C57BL6 mice were subjected to ICR and concomitant single intraperitoneal antibiotic injection. Intestinal lumen contents were collected from jejunum and colon at 7, 14, and 28 days after resection and compared to non-ICR controls. Samples were analyzed by 16S rRNA gene pyrosequencing and quantitative PCR. The intestinal microbiota was altered by 7 days after ICR and accompanying antibiotic treatment, with decreased diversity in the colon. Phylogenetic diversity (PD) decreased from 11.8 ± 1.8 in non-ICR controls to 5.9 ± 0.5 in 7-day post-ICR samples. There were also minor effects in the jejunum where PD values decreased from 8.3 ± 0.4 to 7.5 ± 1.4. PCoA analysis indicated that bacterial populations 28 days post-ICR differed significantly from non-ICR controls. Moreover, colon and jejunum bacterial populations were remarkably similar 28 days after resection, whereas the initial communities differed markedly. Firmicutes and Bacteroidetes were the predominant phyla in jejunum and colon before ICR; however, Firmicutes became the vastly predominant phylum in jejunum and colon 28 days after ICR. Although the microbiota returned towards a homeostatic state, with re-establishment of Firmicutes as the predominant phylum, we did not detect Bacteroidetes in the colon 28 days after ICR. In the jejunum Bacteroidetes was detected at a 0.01% abundance after this time period. The changes in jejunal and colonic microbiota induced by ICR and concomitant antibiotic injection may therefore be considered as potential regulators of post-surgical adaptive growth or function, and in a setting of active IBD, potential contributors to post-surgical pathophysiology of disease recurrence.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The insulin receptor (IR) regulates nutrient uptake and utilization in multiple organs, but its role in the intestinal epithelium is not defined. This study developed a mouse model with villin-Cre ...(VC) recombinase-mediated intestinal epithelial cell (IEC)-specific IR deletion (VC-IR(Δ/Δ)) and littermate controls with floxed, but intact, IR (IR(fl/fl)) to define in vivo roles of IEC-IR in mice fed chow or high-fat diet (HFD). We hypothesized that loss of IEC-IR would alter intestinal growth, biomarkers of intestinal epithelial stem cells (IESC) or other lineages, body weight, adiposity, and glucose or lipid handling. In lean, chow-fed mice, IEC-IR deletion did not affect body or fat mass, plasma glucose, or IEC proliferation. In chow-fed VC-IR(Δ/Δ) mice, mRNA levels of the Paneth cell marker lysozyme (Lyz) were decreased, but markers of other differentiated lineages were unchanged. During HFD-induced obesity, IR(fl/fl) and VC-IR(Δ/Δ) mice exhibited similar increases in body and fat mass, plasma insulin, mRNAs encoding several lipid-handling proteins, a decrease in Paneth cell number, and impaired glucose tolerance. In IR(fl/fl) mice, HFD-induced obesity increased circulating cholesterol; numbers of chromogranin A (CHGA)-positive enteroendocrine cells (EEC); and mRNAs encoding Chga, glucose-dependent insulinotrophic peptide (Gip), glucagon (Gcg), Lyz, IESC biomarkers, and the enterocyte cholesterol transporter Scarb1. All these effects were attenuated or lost in VC-IR(Δ/Δ) mice. These results demonstrate that IEC-IR is not required for normal growth of the intestinal epithelium in lean adult mice. However, our findings provide novel evidence that, during HFD-induced obesity, IEC-IR contributes to increases in EEC, plasma cholesterol, and increased expression of Scarb1 or IESC-, EEC-, and Paneth cell-derived mRNAs.
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