Molecular Endocrinology and Diabetes

המעבדה לאנדוקרינולוגיה מולקולרית וסוכרת
Head of the lab:
Prof. Moshe Phillip, MD
Phone: 054-4795995
Lab Manager:
Dr. Galia Gat-Yablonski, PhD
Phone: 03-9376133
Research team:
    Biana Shtaif (MSc)    
    Meytal Bar-Maisels    
    Yasmin Mansour    
Students:
    סטודנטים לתואר שני: חן מנחם    
    Mrs. Michal Foist    
Research Areas:

Research topics in the lab

 

I.    Together with the Institute for Endocrinology and Diabetes, at the Schneider children’s medical center, we are in the middle of a clinical project aiming at identifying children who are at risk for developing type 1 diabetes. Diagnosis of type1 diabetes (T1D) at the pre-clinical stage can prevent episodes of life threatening diabetic ketoacidosis (DKA) occurring in above 30% of newly diagnosed patients in Israel and open the path for future population- based disease prevention. About 80% of the children diagnosed with T1D before the age of 5 have multiple islet antibodies with an estimated progression rate to symptomatic diabetes of 85% by 15 years. Thus, an efficient screening program based on these antibodies will identify children at risk for developing diabetes during childhood, thereby preventing DKA episodes upon clinical presentation, aiding in the search for early, efficient therapy for the disease, as well as enabling caregivers to prepare the children and their families for future insulin treatment. Antibodies will be measured using the Ultrasensitive Antibody Detection by Agglutination-PCR (ADAP) technology. By using this innovative technology in such a large cohort, we anticipate that we will be able to detect antibodies at an earlier age and stage of the disease.

 

II.  Our lab is studying the processes involved in linear growth in children, in close collaboration with the Institute for Endocrinology and Diabetes at the SCMCI. The study aims to decipher novel regulatory mechanisms for enabling the development of better monitoring and treatment modalities, which are much needed in this field. Every year 1500 children with short stature visit our institute, most of them with a normal hormonal profile, therefore we decided to focus our attention on studying the target organ, the epiphyseal growth plate (EGP). Our model is based on the well-known connection between nutrition and linear growth.

1.      We were the first to show that leptin, the satiety hormone secreted from adipocytes directly activates the growth plate. We have shown that leptin administration to food restricted animals compensated for the reduced amount of food, leading to almost normal growth. We have further showed that leptin binds directly to specific receptors in the EGP and activates its known signal transduction pathways including stat3/Jnk/ERK and that it activates the regulatory pathway of Ihh/PthrP. Recently we found that high levels of leptin, especially during puberty activates aromatase enzyme, which acts to produce estrogen from testosterone. This activation leads to growth cessation and premature closure of the EGP, culminating in short stature. These findings were supported by a clinical observation made in our clinic, showing that obese children may sometimes end up with short stature compared to their peers.

2.      Short children may sometimes be treated with growth hormone even in the presence of adequate amount of the hormone, if they are very short. In order to follow their response to treatment, a sensitive biomarker is required, apart from height measuring, as this gives indication only after 6 months or more. We are studying different biomarkers in several setups both clinical and pre-clinical.

3.      Animal studies are performed to study the effect of nutrition on growth. We are using a model of food restriction induced growth attenuation followed by re-feeding in order to cause catch up growth, which is robust than average growth. We were studying the changes in gene expression, identifying the role of the transcription factor HIF1alpha, several micro RNAs and HDACs. This model was also used to identify the effect of specific nutrients on linear growth, we have shown that the identity of the protein in the diet and not only its amount affects the efficiency of linear growth as well as bone quality. To determine the better protein for supporting optimal linear growth, we compared the effect of soy and whey proteins, both proteins contain all essential amino acids  and are considered the best proteins in their categories. Our findings indicate a better effect of whey on linear growth by leading to slower growth with better-organized epiphyseal growth plates and better bone quality.

4.      A transgenic model we developed in which Sirt1 (an HDAC) was specifically knocked down in the EGP showed that the affected animals had significantly less efficient growth and less efficient response to nutritional manipulation.

5.      Furthermore, using the above-mentioned transgenic collagen type II-specific Sirt1 knockout (CKO) mice we found differences in activity and brain function. The transgenic mice had increased anxiety, with less spatial memory and learning capabilities and reduced activity in their home cages. These findings are very important, as children with idiopathic short stature are more likely to have lower IQ, with substantial deficits in working memory than healthy controls; results of the current study suggest that SIRT1 may be the underlying factor connecting growth and brain function.

6.      Inflammatory disease, such as inflammatory bowel disease (IBD) cause growth attenuation. As the incidence of IBD in children is rapidly rising, resolving growth attenuation is an important challenge in the treatment of this disease; treatment options are limited. Growth hormone (GH) replacement therapy is not a feasible option due to GH resistance mediated by pro inflammatory cytokines. Based on our previous studies showing the important role of nutrition on growth we set out to study the effect of nutrition on growth under inflammatory conditions.

7.      Microbiome analysis at different nutritional states revealed that food restriction lead to significant changes in gut microbiota, similar to the differences reported between fat and lean humans. Using several different diets we noted that specific ingredients in the diet, even when calories and macromolecules are similar, significantly affect gut microbiota and growth. These finding enable us to suggest future improvements to the growth stimulating formula that was developed by the clinic

8.        

 

Future studies

1.      Further analysis of the Sirt1 KO mice

2.      Effect of nutrition on linear growth in the absence of GH

3.      Effect of different diets (containing different proteins) on linear growth

4.      Involvement of microbiome in mediation of the effect of nutrition on growth

5.      Identification of specific and sensitive growth biomarkers

 

 

 

 

 

Publications:
Contact details
Galia Gat-Yablonski Mobile: 050-7658446
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