scholarly journals A new plasmid-based microRNA inhibitor system that inhibits microRNA families in transgenic mice and cells: a potential new therapeutic reagent

Gene Therapy ◽  
2016 ◽  
Vol 23 (6) ◽  
pp. 527-542 ◽  
Author(s):  
H Cao ◽  
W Yu ◽  
X Li ◽  
J Wang ◽  
S Gao ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Family Members ◽  
Stable Complex ◽  
Developmental Defects ◽  
Rna Molecules ◽  
Inhibitor System ◽  
Flanking Sequences ◽  
Target Effects ◽  
In Cells

Abstract Current tools for the inhibition of microRNA (miR) function are limited to modified antisense oligonucleotides, sponges and decoy RNA molecules and none have been used to understand miR function during development. CRISPR/Cas-mediated deletion of miR sequences within the genome requires multiple chromosomal deletions to remove all functional miR family members because of duplications. Here, we report a novel plasmid-based miR inhibitor system (PMIS) that expresses a new RNA molecule, which inhibits miR family members in cells and mice. The PMIS engineered RNA optimal secondary structure, flanking sequences and specific antisense miR oligonucleotide sequence bind the miR in a stable complex to inhibit miR activity. In cells, one PMIS can effectively inhibit miR family members that share the same seed sequence. The PMIS shows no off-target effects or toxicity and is highly specific for miRs sharing identical seed sequences. Transgenic mice expressing both PMIS-miR-17-18 and PMIS-miR-19-92 show similar phenotypes of miR-17-92-knockout mice. Interestingly, mice only expressing PMIS-miR-17-18 have developmental defects distinct from mice only expressing PMIS-miR-19-92 demonstrating usefulness of the PMIS system to dissect different functions of miRs within clusters. Different PMIS miR inhibitors can be linked together to knock down multiple miRs expressed from different chromosomes. Inhibition of the miR-17-92, miR-106a-363 and miR-106b-25 clusters reveals new mechanisms and developmental defects for these miRs. We report a new tool to dissect the role of miRs in development without genome editing, inhibit miR function in cells and as a potential new therapeutic reagent.

Role of Bcl-2 Family in Lymphoid Malignancies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. SCI-41-SCI-41
Author(s):  
Andreas Strasser ◽  
G. Kelly ◽  
S. Glaser ◽  
S. Grabow ◽  
A. Delbridge ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Hematological Malignancies ◽  
Cell Cycle Control ◽  
Family Members ◽  
B Lymphoma ◽  
Over Expression ◽  
Death Studies ◽  
Lymphoid Malignancies ◽  
Single Allele

Abstract Impaired apoptosis is considered one of the prerequisites for the development of most, if not all, cancers, but the mechanisms that guarantee the sustained survival of most cancer cells remain unknown. Members of the Bcl-2 family are key regulators of apoptosis and include proteins essential for cell survival and those required to initiate cell death. Studies with transgenic mice have shown that over-expression of Bcl-2 or related pro-survival family proteins, such as Bcl-xL or Mcl-1, can promote tumorigenesis, particularly in conjunction with mutations that deregulate cell cycle control, such as deregulated c-myc expression. It is, however, not known whether expression of pro-survival Bcl-2 family members under endogenous control is required to maintain the survival of cells undergoing neoplastic transformation. Using Eµ-myc transgenic mice, a well-characterized model of human Burkitt’s lymphoma, we investigated the role of endogenous Bcl-2 in lymphoma development. Bcl-2 was found to be dispensable for the development of Eµ-myc pre-B/B lymphoma. In contrast, loss of Bcl-xL and even, more remarkable, loss of a single allele of Mcl1 greatly impaired lymphoma development. Experiments with inducible knockout mice demonstrated that Mcl-1 but not Bcl-xL is essential for the sustained survival and expansion of Myc-driven malignant pore-B/B lymphoma. Remarkably, even loss of one Mcl1allele greatly impaired lymphoma growth. These findings were translated into using lymphoid malignancies by using inducible expression of selective antagonists of distinct pro-survival Bcl-2 family members. Such studies showed that Mcl-1 is also critical for the sustained survival and expansion of Burkitt Lymphoma, a Myc-driven malignancy. These observations indicate that (even relatively weak) targeting of Mcl-1 may be an attractive strategy for the treatment of Myc-driven hematological malignancies. Disclosures: Strasser: Genentech Inc: Consultancy.

scholarly journals Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation

2007 ◽  
Vol 204 (11) ◽  
pp. 2603-2614 ◽  
Author(s):  
Hal Blumberg ◽  
Huyen Dinh ◽  
Esther S. Trueblood ◽  
James Pretorius ◽  
David Kugler ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Inflammatory Cell ◽  
Family Members ◽  
Skin Inflammation ◽  
Antagonistic Activity ◽  
Psoriatic Skin ◽  
Inflammatory Cell Infiltrate ◽  
Skin Abnormalities

The interleukin (IL)-1 family members IL-1α, -1β, and -18 are potent inflammatory cytokines whose activities are dependent on heterodimeric receptors of the IL-1R superfamily, and which are regulated by soluble antagonists. Recently, several new IL-1 family members have been identified. To determine the role of one of these family members in the skin, transgenic mice expressing IL1F6 in basal keratinocytes were generated. IL1F6 transgenic mice exhibit skin abnormalities that are dependent on IL-1Rrp2 and IL-1RAcP, which are two members of the IL-1R family. The skin phenotype is characterized by acanthosis, hyperkeratosis, the presence of a mixed inflammatory cell infiltrate, and increased cytokine and chemokine expression. Strikingly, the combination of the IL-1F6 transgene with an IL1F5 deficiency results in exacerbation of the skin phenotype, demonstrating that IL-1F5 has antagonistic activity in vivo. Skin from IL1F6 transgenic, IL1F5−/− pups contains intracorneal and intraepithelial pustules, nucleated corneocytes, and dilated superficial dermal blood vessels. Additionally, expression of IL1RL2, -1F5, and -1F6 is increased in human psoriatic skin. In summary, dysregulated expression of novel agonistic and antagonistic IL-1 family member ligands can promote cutaneous inflammation, revealing potential novel targets for the treatment of inflammatory skin disorders.

scholarly journals Nephronophthisis gene products display RNA-binding properties and are recruited to stress granules

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Luisa Estrada Mallarino ◽  
Christina Engel ◽  
İbrahim Avşar Ilık ◽  
Daniel Maticzka ◽  
Florian Heyl ◽  
...  
Keyword(s):  
Stress Responses ◽  
Rna Binding ◽  
Family Members ◽  
Stress Granules ◽  
Binding Properties ◽  
Developmental Defects ◽  
Rna Molecules ◽  
Tissue Integrity ◽  
Repeat Proteins ◽  
Ankyrin Repeat Proteins

Abstract Mutations of cilia-associated molecules cause multiple developmental defects that are collectively termed ciliopathies. However, several ciliary proteins, involved in gating access to the cilium, also assume localizations at other cellular sites including the nucleus, where they participate in DNA damage responses to maintain tissue integrity. Molecular insight into how these molecules execute such diverse functions remains limited. A mass spectrometry screen for ANKS6-interacting proteins suggested an involvement of ANKS6 in RNA processing and/or binding. Comparing the RNA-binding properties of the known RNA-binding protein BICC1 with the three ankyrin-repeat proteins ANKS3, ANKS6 (NPHP16) and INVERSIN (NPHP2) confirmed that certain nephronophthisis (NPH) family members can interact with RNA molecules. We also observed that BICC1 and INVERSIN associate with stress granules in response to translational inhibition. Furthermore, BICC1 recruits ANKS3 and ANKS6 into TIA-1-positive stress granules after exposure to hippuristanol. Our findings uncover a novel function of NPH family members, and provide further evidence that NPH family members together with BICC1 are involved in stress responses to maintain tissue and organ integrity.

The Role of Family Members in Safer/Unsafe Injection Drug Use Practices

2011 ◽  
Author(s):  
L. Jackson ◽  
M. Dykeman ◽  
J. Gahagan ◽  
J. Karabanow ◽  
J. Parker
Keyword(s):  
Drug Use ◽  
Injection Drug Use ◽  
Family Members ◽  
Injection Drug ◽  
Unsafe Injection

Pembinaan Semula Peradaban Komuniti Cina Muslim Berasaskan Dialog Antara Agama: Pengalaman di Terengganu dan Brunei

Sains Insani ◽  
2019 ◽  
Vol 4 (1) ◽  
pp. 77-84
Author(s):  
Azarudin Awang ◽  
Azman Che Mat ◽  
Sophian Ramli
Keyword(s):  
Cultural Practices ◽  
Family Members ◽  
Interfaith Dialogue ◽  
Chinese Community ◽  
Cultural Life ◽  
Muslim Communities ◽  
Muslim Family

Bagi sesebuah negara yang mempunyai etnik pelbagai anutan kepercayaan dan perbezaan amalan budaya, dialog antara agama berperanan membetulkan semula kekaburan dalam kehidupan beragama dan berbudaya. Melalui peranan Saudara Baru, dialog antara agama mampu menjadi medan bagi menjelaskan kebenaran tentang agama Islam kepada masyarakat bukan Muslim dan pelaksanaan amalan budaya asal kepada Muslim asal. Objektif kajian ini ialah melihat pengalaman pelaksanaan dialog antara agama di Terengganu dan relevansi dalam kehidupan beragama di negara Brunei. Metode kajian ini menggunakan kajian dokumen yang menyentuh komuniti Cina Muslim di Terengganu dan Brunei. Pengalaman pelaksanaan dialog antara agama di Terengganu dan negara Brunei memperlihatkan dialog antara agama mampu membetulkan salah faham dan selanjutnya mengendurkan ketegangan hubungan antara agama dan budaya antara komuniti Saudara Baru, ahli keluarga bukan Muslim dan masyarakat Muslim asal. Biarpun begitu, adalah dicadangkan agar kajian yang menyentuh dialog antara agama perlu diperkukuhkan sebagai medium membina semula peradaban memandangkan penduduk di kedua-dua lokasi ini terdiri daripada berbilang etnik dan agama sedangkan pada masa yang sama masalah yang menyentuh hubungan antara agama sentiasa timbul. Abstract: For a country with diverse ethics of beliefs and cultural practices, interfaith dialogue plays a role to redefine ambiguity in religious and cultural life. Through the role of the New Muslim (Muslim Convert), interfaith dialogue can become a medium to explain the truth about Islam to the non-Muslims and the implementation of real cultural practices to the others Muslim. The objective of this study is to examine the experience of interfaith dialogue in Terengganu and in Brunei. The method of this study is being conducted in document research that related with the Muslim Chinese community in Terengganu and Brunei. In addition, interviews with people involved in the management of New Muslims also carried out. The experience of interfaith dialogue in Terengganu and Brunei shows that dialogue capable explains misunderstandings and further loosening the tension between religion and culture among New Muslims, non-Muslim family members and Muslim communities. However, it is recommended that studies on interfaith dialogue should be strengthened as a medium for rebuilding civilization as the residents of both locations are multi-ethnic and religious while at the same time the problem of interreligious persists.

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