المتابعون

الأربعاء، 7 سبتمبر، 2011

د أحمد الحشاش


موجز للسيرة الذاتية للعالم المصري
د/ أحمد خليفة الحشاش

تقديم : الحجامة الرياضية : د/ أحمد حلمي صالح

الدكتور / أحمد خليفة الحشاش
ولد بقرية القضابة – مركز بسيون – محافظة الغربية.
تلقى تعليمه الابتدائي بمدرسة القضابة الابتدائية
وتلقى تعليمه الاعدادى بمدرسة صلاح حتاتة الإعدادية ببسيون.
وتعليمه الثانوي بمدرسة ناصر الثانوية ببسيون
**بكالوريوس علوم طنطا سنة 1991
**ماجستير العلوم جامعة طنطا
**دكتوراه علم الأجنة جامعة مانشستر سنة 2005-انجلترا-
** عمل مدرسا فى جامعة كاردف 2005 - 2006 – بريطانيا.
** عمل مدرسا فى كلية طب جامعة نيويورك من 2006 -2008
** ثم أستاذا  مساعدا فى كلية طب جامعة جنوب كاليفورنيا-لوس انجلوس-أمريكا2008 حتى الآن.
**حصل على إحدى جوائز أفضل طالب دكتوراه من جامعة مانشستر - انجلترا
**حصل على جائزة التميز من معهد كاليفورنيا للطب التعويضي
**له 17 بحثا علميا منشورا فى مجال علم الأجنة والخلايا الجذعية.
**ألقى العديد من المحاضرات العلمية فى مؤتمرات متعددة فى تخصصه وآخرها دعوة لحضور مؤتمر فى الصين بعنوان (الخلايا الجذعية ودورها فى علاج الأمراض).
عضو فى الجمعية الأمريكية للصدر
وعضو فى الجمعية الأمريكية لعلم الأجنة.

من كلمات الدكتور أحمد الحشاش 

لابد من توافق الرغبة مع قدرات الأنسان لتحقيق هذه الرغبة.
العمل جزء كبير من العبادة . ( يتشابه قول الدكتور مع قول مواطنه الفريق سعد الدين الشاذلي رحمة الله بقوله : أن الأيمان جزء كبيرمن النصر)


 (ابحث على الروابط الآتية للاسترشاد تتحدث عن  الدكتور أحمد الحشاش)
http://www.shorouknews.com/ContentData.aspx?id=465892
http://www.shorouknews.com/contentData.aspx?id=427436
http://www.youtube.com/watch?v=N_WBNQ2FoCE
أحد الحلقات التليفزيونية مع الدكتور أحمد الحشاش مكتشف مفتاح الخلية الجذعية  : http://www.youtube.com/watch?v=q6lIUUh4PNA

ننفرد بنشر ملخصات أبحاث العالم المصري دكتور / أحمد الحشاش مكتشف مفتاح الخلية الجذعية . 

 
Mech Dev. 2010 Jan-Feb;127(1-2):1-20. Epub 2009 Sep 13.

Genes and signals regulating murine trophoblast cell development.

Developmental Biology, Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA 90027, USA.

Abstract

A fundamental step in embryonic development is cell differentiation whereby highly specialised cell types are developed from a single undifferentiated, fertilised egg. One of the earliest lineages to form in the mammalian conceptus is the trophoblast, which contributes exclusively to the extraembryonic structures that form the placenta. Trophoblast giant cells (TGCs) in the rodent placenta form the outermost layer of the extraembryonic compartment, establish direct contact with maternal cells, and produce a number of pregnancy-specific cytokine hormones. Giant cells differentiate from proliferative trophoblasts as they exit the cell cycle and enter a genome-amplifying endocycle. Normal differentiation of secondary TGCs is a critical step toward the formation of the placenta and normal embryonic development. Trophoblast development is also of particular interest to the developmental biologist and immunobiologist, as these cells constitute the immediate cellular boundary between the embryonic and maternal tissues. Abnormalities in the development of secondary TGCs results in severe malfunction of the placenta. Herein we review new information that has been accumulated recently regarding the molecular and cellular regulation of trophoblast and placenta development. In particular, we discuss the molecular aspects of murine TGC differentiation. We also focus on the role of growth and transcription factors in TGC development.
Copyright 2009 Elsevier Ireland Ltd. All rights reserved.
Dev Biol. 2011 Feb 1;350(1):112-26. Epub 2010 Dec 1.

Eyes absent 1 (Eya1) is a critical coordinator of epithelial, mesenchymal and vascular morphogenesis in the mammalian lung.

Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Childrens Hospital Los Angeles, Keck School of Medicine of University of Southern California, 4650 Sunset Boulevard MS35, Los Angeles, CA 90027, USA.

Abstract

The proper level of proliferation and differentiation along the proximodistal axis is crucial for lung organogenesis. Elucidation of the factors that control these processes will therefore provide important insights into embryonic lung development and regeneration. Eya1 is a transcription factor/protein phosphatase that regulates cell lineage specification and proliferation. Yet its functions during lung development are unknown. In this paper we show that Eya1(-/-) lungs are severely hypoplastic with reduced epithelial branching and increased mesenchymal cellularity. Eya1 is expressed at the distal epithelial tips of branching tubules as well as in the surrounding distal mesenchyme. Eya1(-/-) lung epithelial cells show loss of progenitor cell markers with increased expression of differentiation markers and cell cycle exit. In addition, Eya1(-/-) embryos and newborn mice exhibit severe defects in the smooth muscle component of the bronchi and major pulmonary vessels with decreased Fgf10 expression. These defects lead to rupture of the major vessels and hemorrhage into the lungs after birth. Treatment of Eya1(-/-) epithelial explants in culture with recombinant Fgf10 stimulates epithelial branching. Since Shh expression and activity are abnormally increased in Eya1(-/-) lungs, we tested whether genetically lowering Shh activity could rescue the Eya1(-/-) lung phenotype. Indeed, genetic reduction of Shh partially rescues Eya1(-/-) lung defects while restoring Fgf10 expression. This study provides the first evidence that Eya1 regulates Shh signaling in embryonic lung, thus ensuring the proper level of proliferation and differentiation along the proximodistal axis of epithelial, mesenchymal and endothelial cells. These findings uncover novel functions for Eya1 as a critical upstream coordinator of Shh-Fgf10 signaling during embryonic lung development. We conclude, therefore, that Eya1 function is critical for proper coordination of lung epithelial, mesenchymal and vascular development.
Copyright © 2010 Elsevier Inc. All rights reserved.
Development. 2011 Apr;138(7):1395-407.

Eya1 controls cell polarity, spindle orientation, cell fate and Notch signaling in distal embryonic lung epithelium.

Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Childrens Hospital Los Angeles, Keck School of Medicine of University of Southern California, 4661 Sunset Boulevard, Los Angeles, CA 90027, USA.

Abstract

Cell polarity, mitotic spindle orientation and asymmetric division play a crucial role in the self-renewal/differentiation of epithelial cells, yet little is known about these processes and the molecular programs that control them in embryonic lung distal epithelium. Herein, we provide the first evidence that embryonic lung distal epithelium is polarized with characteristic perpendicular cell divisions. Consistent with these findings, spindle orientation-regulatory proteins Insc, LGN (Gpsm2) and NuMA, and the cell fate determinant Numb are asymmetrically localized in embryonic lung distal epithelium. Interfering with the function of these proteins in vitro randomizes spindle orientation and changes cell fate. We further show that Eya1 protein regulates cell polarity, spindle orientation and the localization of Numb, which inhibits Notch signaling. Hence, Eya1 promotes both perpendicular division as well as Numb asymmetric segregation to one daughter in mitotic distal lung epithelium, probably by controlling aPKCζ phosphorylation. Thus, epithelial cell polarity and mitotic spindle orientation are defective after interfering with Eya1 function in vivo or in vitro. In addition, in Eya1(-/-) lungs, perpendicular division is not maintained and Numb is segregated to both daughter cells in mitotic epithelial cells, leading to inactivation of Notch signaling. As Notch signaling promotes progenitor cell identity at the expense of differentiated cell phenotypes, we test whether genetic activation of Notch could rescue the Eya1(-/-) lung phenotype, which is characterized by loss of epithelial progenitors, increased epithelial differentiation but reduced branching. Indeed, genetic activation of Notch partially rescues Eya1(-/-) lung epithelial defects. These findings uncover novel functions for Eya1 as a crucial regulator of the complex behavior of distal embryonic lung epithelium.

Dev Dyn. 2011 Feb;240(2):441-5. doi: 10.1002/dvdy.22551.

Cell polarity and spindle orientation in the distal epithelium of embryonic lung.

Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, California, USA.

Abstract

A proper balance between self-renewal and differentiation of lung-specific progenitors at the distal epithelial tips is absolutely required for normal lung morphogenesis. Cell polarity and mitotic spindle orientation play a critical role in the self-renewal/differentiation of epithelial cells and can impact normal physiological processes, including epithelial tissue branching and differentiation. Therefore, understanding the behavior of lung distal epithelial progenitors could identify innovative solutions to restoring normal lung morphogenesis. Yet little is known about cell polarity, spindle orientation, and segregation of cell fate determinant in the embryonic lung epithelium, which contains progenitor cells. Herein, we provide the first evidence that embryonic lung distal epithelium is polarized and highly mitotic with characteristic perpendicular cell divisions. Consistent with these findings, mInsc, LGN, and NuMA polarity proteins, which control spindle orientation, are asymmetrically localized in mitotic distal epithelial progenitors of embryonic lungs. Furthermore, the cell fate determinant Numb is asymmetrically distributed at the apical side of distal epithelial progenitors and segregated to one daughter cell in most mitotic cells. These findings provide evidence for polarity in distal epithelial progenitors of embryonic lungs and provide a framework for future translationally oriented studies in this area.
Copyright © 2011 Wiley-Liss, Inc.
Curr Top Dev Biol. 2010;90:73-158.

Lung organogenesis.

The Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, California, USA.

Abstract

Developmental lung biology is a field that has the potential for significant human impact: lung disease at the extremes of age continues to cause major morbidity and mortality worldwide. Understanding how the lung develops holds the promise that investigators can use this knowledge to aid lung repair and regeneration. In the decade since the "molecular embryology" of the lung was first comprehensively reviewed, new challenges have emerged-and it is on these that we focus the current review. Firstly, there is a critical need to understand the progenitor cell biology of the lung in order to exploit the potential of stem cells for the treatment of lung disease. Secondly, the current familiar descriptions of lung morphogenesis governed by growth and transcription factors need to be elaborated upon with the reinclusion and reconsideration of other factors, such as mechanics, in lung growth. Thirdly, efforts to parse the finer detail of lung bud signaling may need to be combined with broader consideration of overarching mechanisms that may be therapeutically easier to target: in this arena, we advance the proposal that looking at the lung in general (and branching in particular) in terms of clocks may yield unexpected benefits.
Copyright 2010 Elsevier Inc. All rights reserved.
Dev Biol. 2009 Sep 15;333(2):238-50. Epub 2009 Jun 25.

miR-17 family of microRNAs controls FGF10-mediated embryonic lung epithelial branching morphogenesis through MAPK14 and STAT3 regulation of E-Cadherin distribution.

Developmental Biology, Regenerative Medicine and Surgery Program, Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine and School of Dentistry, Los Angeles, CA 90027, USA.

Abstract

The miR-17 family of microRNAs has recently been recognized for its importance during lung development. The transgenic overexpression of the entire miR-17-92 cluster in the lung epithelium led to elevated cellular proliferation and inhibition of differentiation, while targeted deletion of miR-17-92 and miR-106b-25 clusters showed embryonic or early post-natal lethality. Herein we demonstrate that miR-17 and its paralogs, miR-20a, and miR-106b, are highly expressed during the pseudoglandular stage and identify their critical functional role during embryonic lung development. Simultaneous downregulation of these three miRNAs in explants of isolated lung epithelium altered FGF10 induced budding morphogenesis, an effect that was rescued by synthetic miR-17. E-Cadherin levels were reduced, and its distribution was altered by miR-17, miR-20a and miR-106b downregulation, while conversely, beta-catenin activity was augmented, and expression of its downstream targets, including Bmp4 as well as Fgfr2b, increased. Finally, we identified Stat3 and Mapk14 as key direct targets of miR-17, miR-20a, and miR-106b and showed that simultaneous overexpression of Stat3 and Mapk14 mimics the alteration of E-Cadherin distribution observed after miR-17, miR-20a, and miR-106b downregulation. We conclude that the mir-17 family of miRNA modulates FGF10-FGFR2b downstream signaling by specifically targeting Stat3 and Mapk14, hence regulating E-Cadherin expression, which in turn modulates epithelial bud morphogenesis in response to FGF10 signaling.


Dev Biol. 2006 Feb 1;290(1):13-31. Epub 2005 Dec 20.

PTHrP induces changes in cell cytoskeleton and E-cadherin and regulates Eph/Ephrin kinases and RhoGTPases in murine secondary trophoblast cells.

Faculty of Life Sciences, University of Manchester, 3.239 Stopford Building, Oxford Road, Manchester M13 9PT, UK. El-HashashA@cardiff.ac.uk

Abstract

The differentiation of murine trophoblast giant cells (TGCs) is well characterised at the molecular level and, to some extent, the cellular level. Currently, there is a rudimentary understanding about factors regulating the cellular differentiation of secondary TGCs. Using day 8.5 p.c.-ectoplacental cone (EPC) explant in serum-free culture, we have found parathyroid hormone-related protein (PTHrP) to regulate cellular changes during TGC differentiation. PTHrP greatly stimulated the formation and organisation of actin stress fibres and actin expression in trophoblast outgrowth. This coincided with changing cell shape into a flattened/fibroblastic morphology, suppression of E-cadherin expression, and increased cell spreading in culture. PTHrP also increased the nuclear staining of beta-catenin and, similar to activator protein-2gamma (AP-2gamma), showed microtubule-dependent nuclear localisation in vitro. These cellular and behavioural changes correlated with changes in the expression of RhoGTPases and in both expression and phosphorylation of Eph/Ephrin kinases. The effects of PTHrP on trophoblast cellular differentiation were abolished after blocking its action. In conclusion, PTHrP provides an excellent example of the extrinsic factors that, through their network of activities, plays an important role in cellular differentiation of secondary TGCs.

Differentiation. 2005 Apr;73(4):154-74.

PTHrP promotes murine secondary trophoblast giant cell differentiation through induction of endocycle, upregulation of giant-cell-promoting transcription factors and suppression of other trophoblast cell types.

Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.

Abstract

The murine trophoblast cell lineage represents an intriguing experimental cell model as it is composed of four trophoblast stem (TS)-derived cell types: trophoblast giant cells (TGCs), spongiotrophoblast, syncytotrophoblast, and glycogen trophoblast cells. To investigate the role of parathyroid hormone-related protein (PTHrP) in TGC differentiation, we analyzed the effect of exogenous PTHrP on secondary TGCs of day 8.5 p.c. ectoplacental cone explant culture. Secondary TGCs expressed PTHrP and PTHR1 receptor in vivo and in vitro. TGCs treated with PTHrP had reduced proliferation and decreased apoptosis starting from day 2 in culture, and enhanced properties of giant cell differentiation: increased DNA synthesis, number of cells with giant nuclei and expression of placental lactogen-II (PL-II). The induction of TGC formation by PTHrP correlated with downregulation of cyclin B1 and mSNA expression, but upregulation of cyclin D1, thus allowing mitotic-endocycle transition. Moreover, PTHrP treatment influenced TGC differentiation by inducing the expression of transcription factors known to stimulate giant cell formation: Stra13 and AP-2gamma, and inhibiting the formation of other trophoblast cell types by suppressing trophoblast progenitors and spongiotrophoblast-promoting factors, Eomes, Mash-2, and mSNA. Taken together with the spatial and temporal patterns of TGC formation and PTHrP synthesis in vivo, these findings indicate an important role for PTHrP in the differentiation of secondary TGCs during placentation.

Dev Biol. 2011 Apr 1;352(1):141-51. Epub 2011 Jan 31.

Six1 regulates Grem1 expression in the metanephric mesenchyme to initiate branching morphogenesis.

Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of NYU, New York, NY10029, USA.

Abstract

Urinary tract morphogenesis requires subdivision of the ureteric bud (UB) into the intra-renal collecting system and the extra-renal ureter, by responding to signals in its surrounding mesenchyme. BMP4 is a mesenchymal regulator promoting ureter development, while GREM1 is necessary to negatively regulate BMP4 activity to induce UB branching. However, the mechanisms that regulate the GREM1-BMP4 signaling are unknown. Previous studies have shown that Six1-deficient mice lack kidneys, but form ureters. Here, we show that the tip cells of Six1(-/-) UB fail to form an ampulla for branching. Instead, the UB elongates within Tbx18- and Bmp4-expressing mesenchyme. We find that the expression of Grem1 in the metanephric mesenchyme (MM) is Six1-dependent. Treatment of Six1(-/-) kidney rudiments with GREM1 protein restores ampulla formation and branching morphogenesis. Furthermore, we demonstrate that genetic reduction of BMP4 levels in Six1(-/-) (Six1(-/-); Bmp4(+/-)) embryos restores urinary tract morphogenesis and kidney formation. This study uncovers an essential function for Six1 in the MM as an upstream regulator of Grem1 in initiating branching morphogenesis.
Copyright © 2011 Elsevier Inc. All rights reserved.
Dev Biol. 2011 Mar 6. [Epub ahead of print]

Six1 transcription factor is critical for coordination of epithelial, mesenchymal and vascular morphogenesis in the mammalian lung.

Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, 4650 Sunset Boulevard MS35, Los Angeles, CA 90027, USA.

Abstract

Six1 is a member of the six-homeodomain family of transcription factors. Six1 is expressed in multiple embryonic cell types and plays important roles in proliferation, differentiation and survival of precursor cells of different organs, yet its function during lung development was hitherto unknown. Herein we show that Six1(-/-) lungs are severely hypoplastic with greatly reduced epithelial branching and increased mesenchymal cellularity. Six1 is expressed at the distal epithelial tips of branching tubules as well as in the surrounding distal mesenchyme. Six1(-/-) lung epithelial cells show increased expression of differentiation markers, but loss of progenitor cell markers. Six1 overexpression in MLE15 lung epithelial cells in vitro inhibited cell differentiation, but increases the expression of progenitor cell markers. In addition, Six1(-/-) embryos and newborn mice exhibit mesenchymal overproliferation, decreased Fgf10 expression and severe defects in the smooth muscle component of the bronchi and major pulmonary vessels. These defects lead to rupture of major vessels in mutant lungs after birth. Treatment of Six1(-/-) epithelial explants in culture with recombinant Fgf10 protein restores epithelial branching. As Shh expression is abnormally increased in Six1(-/-) lungs, we also treated mutant mesenchymal explants with recombinant Shh protein and found that these explants were competent to respond to Shh and continued to grow in culture. Furthermore, inhibition of Shh signaling with cyclopamine stimulated Six1(-/-) lungs to grow and branch in culture. This study provides the first evidence for the requirement of Six1 in coordinating Shh-Fgf10 signaling in embryonic lung to ensure proper levels of proliferation and differentiation along the proximodistal axis of epithelial, mesenchymal and endothelial cells. These findings uncover novel and essential functions for Six1 as a critical coordinator of Shh-Fgf10 signaling during embryonic lung development. We propose that Six1 is hence critical for coordination of proper lung epithelial, mesenchymal and vascular development.




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