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