Biology subjects

Raz, M.

Publications and source records attributed to Raz, M..

7 recordsLinked to original sources

bioRxiv2024

Unifying regulatory motifs in endocrine circuits

In this study we identify unifying design principles in human endocrine systems. We find that 43 hormone systems, controlling diverse physiological functions, fall into 5 classes of circuits with shared structure - thus only a small number of the possible circuits actually occur. Each class uses a different regulatory logic to perform specific dynamical functions, such as homeostasis, acute input-output response or adjustable set points. The circuits employ interactions on two timescales: hormone secretion on the scale of minutes-hours and growth and shrinkage of endocrine gland mass on the scale of months, which impacts the amount of hormone the glands secrete. This two-timescale principle recurs in several classes of circuits, including the most complex class, which has an intermediate gland, the pituitary. We analyze the pituitary circuit in detail and find tradeoffs between endocrine amplification, buffering of hypersecreting tumors, and rapid response times. These unifying principles of regulation build a foundation for systems endocrinology.

systems biology↗

bioRxiv2024

Hormone circuit analysis explains why most HPA drugs fail for mood disorders and predicts the few that work

Elevated cortisol causes morbidity in chronic stress and mood disorders, including metabolic and cardiovascular diseases. There is therefore interest in developing drugs that lower cortisol by targeting its endocrine pathway, the hypothalamic-pituitary-adrenal (HPA) axis. Several promising HPA-modulating drugs have, however, failed to lower long-term cortisol in mood disorders such as major depressive disorder despite their effectiveness in situations where high cortisol is caused by a tumor (Cushings syndrome). Why these drugs failed is not well understood. Here we use a mathematical model of the HPA axis to show that the pituitary and the adrenal glands compensate for the effect of drugs by adjusting their functional mass, a feedback compensation that is absent in Cushing tumors. To find potential drug targets, we carried out a systematic in silico analysis of points of intervention in the HPA axis. We find that only two interventions that target corticotropin-releasing hormone (CRH) can lower long-term cortisol. Other drug targets either fail to lower cortisol due to gland-mass compensation or lower cortisol but harm other aspects of the HPA axis. Thus, we identify potential drug targets, including CRH-neutralizing antibodies and CRH-synthesis inhibitors, for lowering long-term cortisol in mood disorders and in those suffering from chronic stress. More generally, this study indicates that understanding the slow compensatory mechanisms in endocrine axes can be crucial in order to prioritize drug targets.

systems biology↗

bioRxiv2023

Unifying design principles of endocrine gland mass and its regulatory circuits

Hormones are regulatory molecules that impact physiological functions. Much is known about individual hormones, but general rules that connect the regulatory logic of different hormone systems are limited. In this study, we analyzed a range of human hormone systems using a mathematical approach to integrate knowledge on endocrine cells, target tissues and regulation, to uncover unifying principles and regulatory circuits. We find that the number of cells in an endocrine gland is proportional to the number of cells in its target tissues, as one single endocrine cell serves approximately 2000 target cells. We identified five classes of regulatory circuits, each has specific regulatory functions such as homeostasis or allostasis. The most complex class includes an intermediate gland, the pituitary, which can otherwise be considered redundant and exposes to fragilities. We suggest a tradeoff: with the price of fragilities comes advantages -amplification, buffering of hypersecreting tumors, and faster response times. By elucidating these unifying principles and circuits, this study deepens our understanding of the control of endocrine processes and builds the foundation for systems endocrinology.

physiology↗

bioRxiv2022

Genomic alterations drive brain metastases formation in colorectal cancer: The role of IRS2

Colorectal cancer (CRC) is currently the fourth leading etiology of brain metastasis (BM). Yet, mechanisms supporting the formation of CRC BM are mostly unknown. In order to identify drivers that lead to tropism and adaptation of CRC cells to the brain environment, we analyzed an extensive genomic database, consisting of over 36,000 human CRC primary and metastasis samples. Several genomic alterations specific for BM were noted, among them increased prevalence of insulin receptor substrate 2 (IRS2) amplification, observed in 7.6% of BM, compared to only 2.9% of primary tumors or other metastatic sites (p<7E-05). This observation was validated by Immunohistochemistry studies of human clinical samples, showing increased expression of IRS2 protein in BM. IRS2 is a cytoplasmic adaptor mediating effects of insulin and IGF-1 receptors and is involved in more aggressive behavior of different cancer types. In order to study the ability of IRS2 to promote growth of CRC cells under brain microenvironment conditions, we employed an in vitro system consisting of cultured human astrocytes or their conditioned media. Indeed, IRS2-overexpressed CRC cells survived better and formed larger 3D spheres when grown in brain-mimicking conditions, while IRS2-silenced CRC cells showed a mirror image. Similarly, In vivo studies, using intracranial CRC BM mouse model, demonstrated that IRS2-overexpressed cells generated larger brain lesions, while silencing IRS2 dramatically decreased tumor outgrowth and extended survival. Transcriptomic analysis revealed enrichment of oxidative phosphorylation (OXPHOS) and Wnt/{beta}-catenin pathways by IRS2. Indeed, IRS2-expressing cells showed increased mitochondrial activity and glycolysis-independent viability. Furthermore, IRS2-expressing cells had increased {beta}-catenin transcriptional activity, and either {beta}-catenin inhibition or IRS2 inhibition in IRS2-expressing cells decreased their viability, {beta}-catenin transcriptional activity, and mitochondrial activity. These data suggest involvement of IRS2 in modulating OXPHOS through {beta}-catenin. Exploiting this mechanism as a potential vulnerability allowed us to develop novel treatment strategies against CRC BM. NT219 is a novel IRS1/2 inhibitor already being tested in clinical trials. Treatment of mice harboring CRC BM with NT219 and 5-flourouracil reduced tumor growth and prolonged mice survival. These data reveal, for the first time, the unique genomic profile of CRC BM and imply the IRS2 role in promoting CRC BM. These effects may be mediated, at least in part, by modulation of the {beta}-catenin and OXPHOS pathway. These findings may pave the way for clinical trials evaluation this novel IRS2-based strategy for the treatment of CRC BM. Accession no GSE203017 and here is the link: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE203017

cancer biology↗

bioRxiv2020

An opponent process for alcohol addiction based on changes in endocrine gland mass

Consuming addictive drugs is often initially pleasurable, but escalating drug intake eventually recruits physiological "anti-reward" systems called opponent processes that cause tolerance and withdrawal symptoms. Opponent processes are fundamental for the addiction process, but their physiological basis is not fully characterized. Here, we propose an opponent processes mechanism centered on the endocrine stress-response, the HPA axis. We focus on alcohol addiction, where the HPA axis is activated and secretes {beta}-endorphin, causing euphoria and analgesia. Using a mathematical model, we show that slow changes in HPA glands act as an opponent process for {beta}-endorphin secretion. The model explains hormone dynamics in alcohol addiction, and experiments on alcohol preference in rodents. The opponent process is based on fold-change detection (FCD) where {beta}-endorphin responses are relative rather than absolute; FCD confers vulnerability to addiction but has adaptive roles for learning. Our model suggests gland-mass changes as potential targets for intervention in addiction.

systems biology↗

bioRxiv2020

Human hormone seasonality

Hormones control the major biological functions of stress response, growth, metabolism and reproduction. In animals these hormones show pronounced seasonality, with different set-points for different seasons. In humans, the seasonality of these hormones remains unclear, due to a lack of datasets large enough to discern common patterns and cover all hormones. Here, we analyze an Israeli health record on 46 million person-years, including millions of hormone blood tests. We find clear seasonal patterns: the effector hormones peak in winter-spring, whereas most of their upstream regulating pituitary hormones peak only months later, in summer. This delay of months is unexpected because known delays in the hormone circuits last hours. We explain the precise delays and amplitudes by proposing and testing a mechanism for the circannual clock: the gland masses grow with a timescale of months due to trophic effects of the hormones, generating a feedback circuit with a natural frequency of about a year that can entrain to the seasons. Thus, humans may show coordinated seasonal set-points with a winter-spring peak in the growth, stress, metabolism and reproduction axes.

systems biology↗

bioRxiv2020

Hormonal dysregulation after prolonged HPA axis activation can be explained by changes of adrenal and corticotroph masses

Stress activates a complex network of hormones known as the Hypothalamic-Pituitary-Adrenal (HPA) axis. The HPA axis is dysregulated in chronic stress and psychiatric disorders, but the origin of this dysregulation is unclear and cannot be explained by current HPA models. To address this, we developed a new mathematical model for the HPA axis that incorporates changes in the total functional mass of the HPA hormone-secreting glands. The mass changes are caused by the HPA hormones which act as growth factors for the glands in the axis. We find that the HPA axis shows the property of dynamical compensation, where gland masses adjust over weeks to buffer variation in physiological parameters. These mass changes explain the experimental findings on dysregulation of cortisol and ACTH dynamics in alcoholism, anorexia and postpartum. Dysregulation occurs for a wide range of parameters, and is exacerbated by impaired glucocorticoid receptor (GR) feedback, providing an explanation for the implication of GR in mood disorders. These findings suggest that gland-mass dynamics may play an important role in the pathophysiology of stress-related disorders. Author SummaryThe HPA axis is a neuroendocrine axis that is activated in response to stressors. The classical description of this axis includes three hormones that act in a cascade, with the final hormone cortisol inhibiting the two upstream hormones, ACTH and CRH. This classical picture has timescales of hours due to hormone half-lives, and cannot explain phenomena on the scale of weeks to months associated with this axis, such as the dysregulation observed in depression, alcohol addiction, postpartum, and other conditions. Here, we use a minimal-model approach to add to the classical model two known interactions in which CRH and ACTH not only regulate downstream hormones, but also act as growth factors for the cells that secrete these hormones. This creates a physiological circuit that can maintain total cell mass and buffer parameter changes. It has a fragility in which after prolonged stress, the total cell functional masses grow and take weeks to return to baseline. This is sufficient to explain the specific dynamics of hormone dysregulation found in several contexts. It also quantifies the effect of the cortisol (glucocorticoid) receptor on resilience to prolonged stress. Our findings suggest that interactions between hormones and cell functional mass may play an important role in HPA axis regulation on the timescale of weeks to months. Synopsis O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY The HPA axis helps the body adapt to stress, but becomes dysregulated after prolonged activation, with clinical consequences. The origin of this dysregulation is unclear. We provide a mechanism for dysregulation based on the effect of the HPA hormones as growth factors for their downstream glands. O_LIA mathematical model that includes gland functional mass dynamics, introduces a new slow timescale of weeks to the HPA axis; previous models had only fast timescales of hours. C_LIO_LIThe gland masses grow during prolonged activation, providing dynamical compensation, and recover with overshoots over weeks after withdrawal of activation. C_LIO_LIThese overshoots are sufficient to explain the observed HPA dysregulation in pathological conditions, and clarify the role of glucocorticoid receptors in resilience to prolonged stress. C_LI

physiology↗