subject:(CHRFAM7A)

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1. V. Alari. CARATTERIZZAZIONE MOLECOLARE E FUNZIONALE DEL GENE CHRFAM7A, FORMA DUPLICATA DELLA SUBUNITÀ ALPHA7 DEL RECETTORE NICOTINICO.

Degree: 2013, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/215883

The α7 nicotinic acetylcholine receptor (α7 nAChR) has a key role in the innate immune system’s inflammatory response, as part of “cholinergic anti-inflammatory pathway”: a process by which acetylcholine from the vagus nerve reduces the release of the pro-inflammatory cytokine TNFα, thus allowing for a controlled response to infection. The CHRNA7 gene, in humans, is partially duplicated from exon 5-10 and forms an hybrid with four exons (D-A) of a novel gene, FAM7A. This new gene, CHRFAM7A, which is located in the opposite orientation, at 1.6 Mb, from CHRNA7, is not present on every chromosome 15 and a polymorphic variant, in linkage disequilibrium with a 2bp deletion in exon 6, in the same orientation to the CHRNA7 gene, has been described in a cohort of patients with bipolar disorders and schizophrenia. THP-1 monocytic-like cell line expresses only CHRFAM7A, which was down-regulated on treatment with LPS, by a direct transcriptional mechanism reliant on NF-kB. This effect has been confirmed in primary monocytes and macrophages cell cultures, where CHRFAM7A is expressed 200-1000 times more than CHRNA7. Here, the conventional α7 subunit was up-regulated by LPS treatment, thus suggesting the involvement of CHRFAM7A in the regulation of cell surface α7 receptors’ level (a mechanism unique to humans) and the ability of immune cells to respond to acetylcholine, released from the vagus nerve, during infection. This hypothesis seems to be supported by recent works showing that the duplicated form may have a dominant negative effect on the activity of α7 nAChR. Infact, co-expression of CHRFAM7A with α7 results in a significant reduction of the Ach-evoked currents, suggesting the presence of heteromeric non functional receptors at the plasma membrane. The promoter region that regulates the expression of CHRFAM7A is still unknown. To try to identify and characterize this region, 5'-RACE experiments were carried out to map the CHRFAM7A mRNA 5’UTR. RNA was extracted from three different cell lines: THP-1 cells, primary human macrophages and SHSY5Y neuroblastoma cell line. Multiple transcription start sites were identified, depending on the cell line used, suggesting the existence of alternative promoters. A series of constructs that recapitulate the mapping of the CHRFAM7A regulatory region, according to the transcription start sites identified, was also generated. They were cloned into a reporter vector and their functionality was tested by transient transfection both in THP-1 and SHSY5Y cell models. Through these experiments, an intronic region (-702/-208 bp from ATG codon, in exon B) and an Alu sequence (-1155/-821 bp) were identified as negative regulators of reporter gene transcription. Future experiments will allow us to identify other regulatory sites, important for proper CHRFAM7A gene expression in different tissues. Furthermore, two variants exist for CHRFAM7A gene, due to alternative splicing, that gives rise to two protein products of predicted 36 and 47 KDa, whose function is currently unknown. The N-terminally… Advisors/Committee Members: tutor:D. Fornasari, coordinatore: A. Gianni, FORNASARI, DIEGO MARIA MICHELE, GIANNI, ALESSANDRO.

Subjects/Keywords: CHRFAM7A; cholinergic anti-inflammatory pathway; CHRNA7; alpha7; Settore BIO/14 - Farmacologia

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APA (6^th Edition):

Alari, V. (2013). CARATTERIZZAZIONE MOLECOLARE E FUNZIONALE DEL GENE CHRFAM7A, FORMA DUPLICATA DELLA SUBUNITÀ ALPHA7 DEL RECETTORE NICOTINICO. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/215883

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Alari, V.. “CARATTERIZZAZIONE MOLECOLARE E FUNZIONALE DEL GENE CHRFAM7A, FORMA DUPLICATA DELLA SUBUNITÀ ALPHA7 DEL RECETTORE NICOTINICO.” 2013. Thesis, Università degli Studi di Milano. Accessed January 19, 2021. http://hdl.handle.net/2434/215883.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Alari, V.. “CARATTERIZZAZIONE MOLECOLARE E FUNZIONALE DEL GENE CHRFAM7A, FORMA DUPLICATA DELLA SUBUNITÀ ALPHA7 DEL RECETTORE NICOTINICO.” 2013. Web. 19 Jan 2021.

Vancouver:

Alari V. CARATTERIZZAZIONE MOLECOLARE E FUNZIONALE DEL GENE CHRFAM7A, FORMA DUPLICATA DELLA SUBUNITÀ ALPHA7 DEL RECETTORE NICOTINICO. [Internet] [Thesis]. Università degli Studi di Milano; 2013. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/2434/215883.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Alari V. CARATTERIZZAZIONE MOLECOLARE E FUNZIONALE DEL GENE CHRFAM7A, FORMA DUPLICATA DELLA SUBUNITÀ ALPHA7 DEL RECETTORE NICOTINICO. [Thesis]. Università degli Studi di Milano; 2013. Available from: http://hdl.handle.net/2434/215883

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

2. A. Maroli. THE HUMAN-RESTRICTED DUPLICATED FORM OF THE ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR, CHRFAM7A: TRANSCRIPTIONAL REGULATION, ROLE IN INFLAMMATION AND POTENTIAL PHARMACOLOGICAL IMPLICATIONS.

Degree: 2017, Università degli Studi di Milano

URL: http://hdl.handle.net/2434/489077

The α7 nicotine acetylcholine receptor (α7nAChR, CHRNA7) is a homo-pentameric ligand-gated ion channel widely expressed in the Central Nervous System (CNS). Recent evidence has demonstrated its expression also in non-neuronal tissues, including monocytes and macrophages, where it mediates the Cholinergic Anti-Inflammatory Pathway, a neuronal reflex providing the central control of systemic inflammation. Recently, the human-restricted duplicated gene of the α7nAChR, called CHRFAM7A (α7dup) has been discovered. It is the product of the partial duplication and fusion of exon 5-10 of CHRNA7 gene with the novel exons D, C, B and A belonging to the FAM7A gene, of unknown function. The CHRFAM7A gene is expressed in human immune cells and in the CNS and is translated into two proteins, of 45 kDa and 36 kDa, which are the result of alternative splicing. The α7dup protein assembles with the α7 conventional subunits and exerts a dominant negative regulation on the α7nAChR function. The importance of the α7dup protein in the human inflammatory process has been confirmed by the demonstration of its responsiveness to pro-inflammatory stimuli: indeed, the Lipopolysaccharide (LPS) treatment of THP-1 monocytic cells and of human primary monocytes and macrophages down-regulates CHRFAM7A transcript and protein through a transcriptional mechanism reliant on the NF-κB transcription factor. Moreover, unpublished data demonstrated that LPS has the opposite effect on the α7 transcript in monocytes and macrophages, leading to CHRNA7 up-regulation. In this study, we have investigated the transcriptional mechanisms leading to CHRFAM7A expression in the THP-1 monocytic cells and in neuroblastoma SH-SY5Y cells and we demonstrate that the CHRFAM7A gene is endowed with several complex transcriptional mechanisms leading to fine expression modulation, including the presence of alternative and tissue-specific Transcription Start Site (TSS), alternative splicing mechanism, tissue-specific transcriptional elements and intronic silencer elements. Moreover, we demonstrated that the CHRFAM7A down-regulation exerted by LPS involve the chromatin remodeling of CHRFAM7A promoter in THP-1 cells. Increasing evidence has linked CHRNA7 expressional and functional dysregulation to several neurodegenerative disorders, including Alzheimer’s disease. The treatment with the acetylcholinesterase inhibitor Donepezil is effective in temporary ameliorating the cognitive symptoms of AD, by increasing the synaptic levels of ACh and counteracting the cholinergic loss, which is characteristic of AD. However, emerging findings sustained that Donepezil can exert its therapeutic effect also by modulating the immune response and potentiating the Cholinergic Anti-Inflammatory Pathway. So far, the role of CHRFAM7A gene in AD pathogenesis or pharmacological response has not been elucidated. In the present study, we have investigated the expression profile of CHRNA7 and CHRFAM7A genes in human nervous and immune tissues obtained from AD patients, highlighting expressional… Advisors/Committee Members: relatore: G. Pietrini, coordinatore: M. Locati, PIETRINI, GRAZIA, PIETRINI, GRAZIA, LOCATI, MASSIMO.

Subjects/Keywords: CHRFAM7A; CHRNA7; Inflammation; Alzheimer's disease; Settore BIO/14 - Farmacologia

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Maroli, A. (2017). THE HUMAN-RESTRICTED DUPLICATED FORM OF THE ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR, CHRFAM7A: TRANSCRIPTIONAL REGULATION, ROLE IN INFLAMMATION AND POTENTIAL PHARMACOLOGICAL IMPLICATIONS. (Thesis). Università degli Studi di Milano. Retrieved from http://hdl.handle.net/2434/489077

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Maroli, A.. “THE HUMAN-RESTRICTED DUPLICATED FORM OF THE ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR, CHRFAM7A: TRANSCRIPTIONAL REGULATION, ROLE IN INFLAMMATION AND POTENTIAL PHARMACOLOGICAL IMPLICATIONS.” 2017. Thesis, Università degli Studi di Milano. Accessed January 19, 2021. http://hdl.handle.net/2434/489077.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Vancouver:

Maroli A. THE HUMAN-RESTRICTED DUPLICATED FORM OF THE ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR, CHRFAM7A: TRANSCRIPTIONAL REGULATION, ROLE IN INFLAMMATION AND POTENTIAL PHARMACOLOGICAL IMPLICATIONS. [Internet] [Thesis]. Università degli Studi di Milano; 2017. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/2434/489077.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Maroli A. THE HUMAN-RESTRICTED DUPLICATED FORM OF THE ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR, CHRFAM7A: TRANSCRIPTIONAL REGULATION, ROLE IN INFLAMMATION AND POTENTIAL PHARMACOLOGICAL IMPLICATIONS. [Thesis]. Università degli Studi di Milano; 2017. Available from: http://hdl.handle.net/2434/489077

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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