Funding Opportunity PAR-17-203 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to support research projects that examine how inter-organelle communication in cancer cells and/or tumor-associated cells affects cellular function, adaptation, and phenotypic plasticity.

Notice NOT-AI-17-016 from the NIH Guide for Grants and Contracts

Funding Opportunity PA-17-197 from the NIH Guide for Grants and Contracts. Despite significant scientific advancements made in substance use disorder research over the last century, the causes and consequences of drug use in later life remain poorly understood. The intent of this funding opportunity announcement is to support innovative research that examines aspects of marijuana and prescription opioid and benzodiazepine use in adults aged 50 and older. This FOA encourages research that examines the determinants of these types of drug use and/or characterizes the resulting neurobiological alterations, associated behaviors, and public health consequences. This initiative will focus on two distinct populations of older adults: individuals with earlier onset of drug use who are now entering this stage of adult development or individuals who initiate drug use after the age of 50. Applications are encouraged to utilize broad methodologies ranging from basic science, clinical, and epidemiological approaches. The insights gleaned from this initiative are critical to our understanding of the determinants of drug use in later life, as well as its consequences in the aging brain and on behavior. This knowledge may have the potential to identify risk factors and to guide clinical practices in older populations.

Funding Opportunity PA-17-198 from the NIH Guide for Grants and Contracts. Despite significant scientific advancements made in substance use disorder research over the last century, the causes and consequences of drug use in later life remain poorly understood. The intent of this funding opportunity announcement is to support innovative research that examines aspects of marijuana and prescription opioid and benzodiazepine use in adults aged 50 and older. This FOA encourages research that examines the determinants of these types of drug use and/or characterizes the resulting neurobiological alterations, associated behaviors, and public health consequences. This initiative will focus on two distinct populations of older adults: individuals with earlier onset of drug use who are now entering this stage of adult development or individuals who initiate drug use after the age of 50. Applications are encouraged to utilize broad methodologies ranging from basic science, clinical, and epidemiological approaches. The insights gleaned from this initiative are critical to our understanding of the determinants of drug use in later life, as well as its consequences in the aging brain and on behavior. This knowledge may have the potential to identify risk factors and to guide clinical practices in older populations.

Funding Opportunity PA-17-196 from the NIH Guide for Grants and Contracts. Despite significant scientific advancements made in substance use disorder research over the last century, the causes and consequences of drug use in later life remain poorly understood. The intent of this funding opportunity announcement is to support innovative research that examines aspects of marijuana and prescription opioid and benzodiazepine use in adults aged 50 and older. This FOA encourages research that examines the determinants of these types of drug use and/or characterizes the resulting neurobiological alterations, associated behaviors, and public health consequences. This initiative will focus on two distinct populations of older adults: individuals with earlier onset of drug use who are now entering this stage of adult development or individuals who initiate drug use after the age of 50. Applications are encouraged to utilize broad methodologies ranging from basic science, clinical, and epidemiological approaches. The insights gleaned from this initiative are critical to our understanding of the determinants of drug use in later life, as well as its consequences in the aging brain and on behavior. This knowledge may have the potential to identify risk factors and to guide clinical practices in older populations.

Funding Opportunity PA-17-202 from the NIH Guide for Grants and Contracts. This FOA encourages applications for research on hearing health care in adults in support of improving access and affordability. Further research is needed to strengthen the evidence base with a goal of delivering better hearing health care outcomes in adults.

Notice NOT-CA-17-034 from the NIH Guide for Grants and Contracts

Notice NOT-DK-17-009 from the NIH Guide for Grants and Contracts

Notice NOT-HD-17-001 from the NIH Guide for Grants and Contracts

Notice NOT-HG-17-001 from the NIH Guide for Grants and Contracts

Notice NOT-CA-17-040 from the NIH Guide for Grants and Contracts

Notice NOT-CA-17-039 from the NIH Guide for Grants and Contracts

Notice NOT-HL-17-491 from the NIH Guide for Grants and Contracts

Notice NOT-HL-17-490 from the NIH Guide for Grants and Contracts

Notice NOT-CA-17-038 from the NIH Guide for Grants and Contracts

Related Articles

Single-cell analysis of mixed-lineage states leading to a binary cell fate choice.

Nature. 2016 Sep 29;537(7622):698-702

Authors: Olsson A, Venkatasubramanian M, Chaudhri VK, Aronow BJ, Salomonis N, Singh H, Grimes HL

Abstract
Delineating hierarchical cellular states, including rare intermediates and the networks of regulatory genes that orchestrate cell-type specification, are continuing challenges for developmental biology. Single-cell RNA sequencing is greatly accelerating such research, given its power to provide comprehensive descriptions of genomic states and their presumptive regulators. Haematopoietic multipotential progenitor cells, as well as bipotential intermediates, manifest mixed-lineage patterns of gene expression at a single-cell level. Such mixed-lineage states may reflect the molecular priming of different developmental potentials by co-expressed alternative-lineage determinants, namely transcription factors. Although a bistable gene regulatory network has been proposed to regulate the specification of either neutrophils or macrophages, the nature of the transition states manifested in vivo, and the underlying dynamics of the cell-fate determinants, have remained elusive. Here we use single-cell RNA sequencing coupled with a new analytic tool, iterative clustering and guide-gene selection, and clonogenic assays to delineate hierarchical genomic and regulatory states that culminate in neutrophil or macrophage specification in mice. We show that this analysis captured prevalent mixed-lineage intermediates that manifested concurrent expression of haematopoietic stem cell/progenitor and myeloid progenitor cell genes. It also revealed rare metastable intermediates that had collapsed the haematopoietic stem cell/progenitor gene expression programme, instead expressing low levels of the myeloid determinants, Irf8 and Gfi1 (refs 9, 10, 11, 12, 13). Genetic perturbations and chromatin immunoprecipitation followed by sequencing revealed Irf8 and Gfi1 as key components of counteracting myeloid-gene-regulatory networks. Combined loss of these two determinants 'trapped' the metastable intermediate. We propose that mixed-lineage states are obligatory during cell-fate specification, manifest differing frequencies because of their dynamic instability and are dictated by counteracting gene-regulatory networks.

PMID: 27580035 [PubMed - indexed for MEDLINE]

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Transcriptional Regulation by ATOH1 and its Target SPDEF in the Intestine.

Cell Mol Gastroenterol Hepatol. 2017 Jan;3(1):51-71

Authors: Lo YH, Chung E, Li Z, Wan YW, Mahe MM, Chen MS, Noah TK, Bell KN, Yalamanchili HK, Klisch TJ, Liu Z, Park JS, Shroyer NF

Abstract
BACKGROUND & AIMS: The transcription factor atonal homolog 1 (ATOH1) controls the fate of intestinal progenitors downstream of the Notch signaling pathway. Intestinal progenitors that escape Notch activation express high levels of ATOH1 and commit to a secretory lineage fate, implicating ATOH1 as a gatekeeper for differentiation of intestinal epithelial cells. Although some transcription factors downstream of ATOH1, such as SPDEF, have been identified to specify differentiation and maturation of specific cell types, the bona fide transcriptional targets of ATOH1 still largely are unknown. Here, we aimed to identify ATOH1 targets and to identify transcription factors that are likely to co-regulate gene expression with ATOH1.
METHODS: We used a combination of chromatin immunoprecipitation and messenger RNA-based high-throughput sequencing (ChIP-seq and RNA-seq), together with cell sorting and transgenic mice, to identify direct targets of ATOH1, and establish the epistatic relationship between ATOH1 and SPDEF.
RESULTS: By using unbiased genome-wide approaches, we identified more than 700 genes as ATOH1 transcriptional targets in adult small intestine and colon. Ontology analysis indicated that ATOH1 directly regulates genes involved in specification and function of secretory cells. De novo motif analysis of ATOH1 targets identified SPDEF as a putative transcriptional co-regulator of ATOH1. Functional epistasis experiments in transgenic mice show that SPDEF amplifies ATOH1-dependent transcription but cannot independently initiate transcription of ATOH1 target genes.
CONCLUSIONS: This study unveils the direct targets of ATOH1 in the adult intestines and illuminates the transcriptional events that initiate the specification and function of intestinal secretory lineages.

PMID: 28174757 [PubMed - in process]

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Mucosal Expression of Type 2 and Type 17 Immune Response Genes Distinguishes Ulcerative Colitis From Colon-only Crohn's Disease in Treatment-naïve Pediatric Patients.

Gastroenterology. 2017 Jan 26;:

Authors: Rosen MJ, Karns R, Vallance JE, Bezold R, Waddell A, Collins MH, Haberman Y, Minar P, Baldassano RN, Hyams JS, Baker SS, Kellermayer R, Noe JD, Griffiths AM, Rosh JR, Crandall WV, Heyman MB, Mack DR, Kappelman MD, Markowitz J, Moulton DE, Leleiko NS, Walters TD, Kugathasan S, Wilson KT, Hogan SP, Denson LA

Abstract
BACKGROUND & AIMS: There is controversy over the role of the type 2 immune response in pathogenesis of ulcerative colitis (UC)-few data are available from treatment-naïve patients. We investigated whether genes associated with a type 2 immune response in the intestinal mucosa are upregulated in treatment-naïve pediatric patients with UC, compared to patients with Crohn's disease (CD)-associated colitis or without inflammatory bowel disease (IBD), and whether expression levels associate with clinical outcomes.
METHODS: We used a real-time reverse transcription quantitative PCR array to analyze mRNA expression patterns in rectal mucosal samples from 138 treatment-naïve pediatric patients with IBD and macroscopic rectal disease, as well as those from 49 children without IBD (controls), enrolled in a multicenter prospective observational study from 2008 and 2012. Results were validated in real-time reverse transcription quantitative PCR analyses of rectal RNA from and independent cohort of 34 pediatric patients with IBD and macroscopic rectal disease and 17 controls from Cincinnati Children's Hospital Medical Center.
RESULTS: We measured significant increases in mRNAs associated with a type 2 immune response (interleukin 5 gene [IL5], IL13, and IL13RA2) and a type 17 immune response (IL17A and IL23) in mucosal samples from patients with UC compared to patients with colon-only CD. In a regression model, increased expression of IL5 and IL17A mRNAs distinguished patients with UC from patients with colon-only CD (P=.001; area under the receiver operating characteristic curve, 0.72). We identified a gene expression pattern in rectal tissues of patients with UC, characterized by detection of IL13 mRNA, that predicted clinical response to therapy after 6 months (OR, 6.469; 95% CI, 1.553-26.94), clinical response after 12 months (OR, 6.125; 95% CI, 1.330-28.22), and remission after 12 months (OR, 5.333; 95% CI, 1.132-25.12).
CONCLUSION: In an analysis of rectal tissues from treatment-naïve pediatric patients with IBD, we observed activation of a type 2 immune response during the early course of UC. We were able to distinguish patients with UC from those with colon-only CD based on increased mucosal expression of genes that mediate type 2 and type 17 immune responses. Increased expression at diagnosis of genes that mediate a type 2 immune response is associated with response to therapy and remission in pediatric patients with UC.

PMID: 28132889 [PubMed - as supplied by publisher]

Related Articles

Association between IL28B rs12979860 single nucleotide polymorphism and the frequency of colonic Treg in chronically HCV-infected patients.

Arch Virol. 2016 Nov;161(11):3161-9

Authors: Mehta M, Hetta HF, Abdel-Hameed EA, Rouster SD, Hossain M, Mekky MA, Khalil NK, Mohamed WA, El-Feky MA, Ahmed SH, Daef EA, El-Mokhtar MA, Abdelwahab SF, Medhat A, Sherman KE, Shata MT

Abstract
The IL28B gene is associated with spontaneous or treatment-induced HCV viral clearance. However, the mechanism by which the IL28B single nucleotide polymorphism (SNP) affects the extra-hepatic HCV immune responses and its relationship to HCV pathogenesis have not been thoroughly investigated. To examine the mechanism by which IL28B affects HCV clearance. Forty Egyptian patients with chronic HCV infection receiving an Interferon/ribavirin treatment regimen were enrolled into this study. There were two groups: non-responders (NR; n = 20) and sustained virologic responders (SVR; n = 20). The initial plasma HCV viral loads prior to treatment and IL28B genotypes were determined by quantitative RT-PCR and sequencing, respectively. Liver biopsies were examined to determine the inflammatory score and the stage of fibrosis. Colonic regulatory T cell (Treg) frequency was estimated by immunohistochemistry. No significant association between IL28B genotypes and response to therapy was identified, despite an odds ratio of 3.4 to have the TT genotype in NR compared to SVR (95 % confidence interval 0.3-35.3, p = 0.3). Patients with the TT-IL28Brs12979860 genotype (unfavorable genotype) have significantly higher frequencies of colonic Treg compared to the CT (p = 0.04) and CC (p = 0.03) genotypes. The frequency of colonic Treg cells in HCV-infected patients had a strong association with the IL-28B genotype and may have a significant impact on HCV clearance.

PMID: 27544760 [PubMed - indexed for MEDLINE]

Related Articles

Cadherin 26 is an alpha integrin-binding epithelial receptor regulated during allergic inflammation.

Mucosal Immunol. 2017 Jan 04;:

Authors: Caldwell JM, Collins MH, Kemme KA, Sherrill JD, Wen T, Rochman M, Stucke EM, Amin L, Tai H, Putnam PE, Jiménez-Dalmaroni MJ, Wormald MR, Porollo A, Abonia JP, Rothenberg ME

Abstract
Cadherins (CDH) mediate diverse processes critical in inflammation, including cell adhesion, migration, and differentiation. Herein, we report that the uncharacterized cadherin 26 (CDH26) is highly expressed by epithelial cells in human allergic gastrointestinal tissue. In vitro, CDH26 promotes calcium-dependent cellular adhesion of cells lacking endogenous CDHs by a mechanism involving homotypic binding and interaction with catenin family members (alpha, beta, and p120), as assessed by biochemical assays. Additionally, CDH26 enhances cellular adhesion to recombinant integrin α4β7 in vitro; conversely, recombinant CDH26 binds αE and α4 integrins in biochemical and cellular functional assays, respectively. Interestingly, CDH26-Fc inhibits activation of human CD4(+) T cells in vitro including secretion of IL-2. Taken together, we have identified a novel functional CDH regulated during allergic responses with unique immunomodulatory properties, as it binds α4 and αE integrins and regulates leukocyte adhesion and activation, and may thus represent a novel checkpoint for immune regulation and therapy via CDH26-Fc.Mucosal Immunology advance online publication 4 January 2017. doi:10.1038/mi.2016.120.

PMID: 28051089 [PubMed - as supplied by publisher]