Dr. Blacher carried out his B.Sc studies in Life Sciences (2007-2010) and proceeded to Ph.D. in Neuroimmunology (2010-2015) under the Dean’s list honors direct Ph.D. program for outstanding students of Tel-Aviv University, Israel. His postdoctoral studies were carried out at the lab of Prof. Eran Elinav from the Immunology department at the Weizmann Institute of Science, Israel (2015-2018), where he studied the role of the Microbiome-gut-brain axis in the context of neurodegenerative diseases.
Honors & Awards
NOSTER & Science Microbiome Prize, Grand prize winner, Science magazine, The American Association for the Advancement of Science (AAAS), NOSTER (2021)
Marie Sklodowska-Curie European Global Fellowship, European Commission (2020)
Stanford University School of Medicine Dean's Postdoctoral Fellowship, Stanford School of Medicine (2020)
Dean of Faculty Fellowship, Weizmann Institute of Science, Israel. (2017-2019)
Ela Kodesh Cancer Research Institute, Tel-Aviv University, Israel. (2015)
Iafa Keydar Cancer Research Endowment, Tel-Aviv University, Israel. (2015)
Sagol School of Neuroscience, Tel-Aviv University, Israel. (2015)
TAU Cancer Biology Research Center (CBRC), Tel-Aviv University, Israel (2015)
The Life Science Faculty Award for Excellence Achievements in Research, Tel-Aviv University, Israel. (2015)
Adams Super-Center for Brain Studies, Tel-Aviv University, Israel. (2013)
Anat Krauskopf travel fund, Tel-Aviv University, Israel (2013)
Ela Kodesh Cancer Research Institute, Tel-Aviv University, Israel (2013)
TAU Cancer Biology Research Center (CBRC), Tel-Aviv University, Israel. (2012)
The Dean’s list honors direct Ph.D. program for outstanding students. The Argentina foundation., Tel-Aviv University, Israel (2011-2015)
Constantiner institute for molecular genetics, Tel-Aviv University, Israel (2010)
Dean award for excellence, Tel-Aviv University, Israel. (2010)
Aging disrupts circadian gene regulation and function in macrophages.
Aging is characterized by an increased vulnerability to infection and the development of inflammatory diseases, such as atherosclerosis, frailty, cancer and neurodegeneration. Here, we find that aging is associated with the loss of diurnally rhythmic innate immune responses, including monocyte trafficking from bone marrow to blood, response to lipopolysaccharide and phagocytosis. This decline in homeostatic immune responses was associated with a striking disappearance of circadian gene transcription in aged compared to young tissue macrophages. Chromatin accessibility was significantly greater in young macrophages than in aged macrophages; however, this difference did not explain the loss of rhythmic gene transcription in aged macrophages. Rather, diurnal expression of Kruppel-like factor 4 (Klf4), a transcription factor (TF) well established in regulating cell differentiation and reprogramming, was selectively diminished in aged macrophages. Ablation of Klf4 expression abolished diurnal rhythms in phagocytic activity, recapitulating the effect of aging on macrophage phagocytosis. Examination of individuals harboring genetic variants of KLF4 revealed an association with age-dependent susceptibility to death caused by bacterial infection. Our results indicate that loss of rhythmic Klf4 expression in aged macrophages is associated with disruption of circadian innate immune homeostasis, a mechanism that may underlie age-associated loss of protective immune responses.
View details for DOI 10.1038/s41590-021-01083-0
View details for PubMedID 34949832
- Can microbes combat neurodegeneration? Science (New York, N.Y.) 2021; 373 (6551): 172-173
CD38 in cancer-associated fibroblasts promotes pro-tumoral activity.
Laboratory investigation; a journal of technical methods and pathology
Primary and metastatic melanoma progression are supported by a local microenvironment comprising, inter alia, of cancer-associated fibroblasts (CAFs). We previously reported in orthotropic/syngeneic mouse models that the stromal ectoenzyme CD38 participates in melanoma growth and metastasis. The results presented here suggest that CD38 is a novel regulator of CAFs' pro-tumorigenic functions. Orthotopic co-implantation of CD38 deficient fibroblasts and B16F10 melanoma cells limited tumor size, compared with CD38-expressing fibroblasts. Intrinsically, CAF-CD38 promoted migration of primary fibroblasts toward melanoma cells. Further, in vitro paracrine effects of CAF-CD38 fostered tumor cell migration and invasion as well as endothelial cell tube formation. Mechanistically, we report that CAF-CD38 drives the protein expression of an angiogenic/pro-metastatic signature, which includes VEGF-A, FGF-2, CXCL-12, MMP-9, and HGF. Data suggest that CAF-CD38 fosters tumorigenesis by enabling the production of pro-tumoral factors that promote cell invasion, migration, and angiogenesis.
View details for DOI 10.1038/s41374-020-0458-8
View details for PubMedID 32612286
Potential roles of gut microbiome and metabolites in modulating ALS in mice.
Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder, in which the clinical manifestations may be influenced by genetic and unknown environmental factors. Here we show that ALS-prone Sod1 transgenic (Sod1-Tg) mice have a pre-symptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. We correlate eleven distinct commensal bacteria at our vivarium with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1-Tg mice we demonstrate that Akkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS. Furthermore, Sod1-Tg mice that are administered AM are found to accumulate AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improves motor symptoms and gene expression patterns in the spinal cord of Sod1-Tg mice. In humans, we identify distinct microbiome and metabolite configurations-including reduced levels of nicotinamide systemically and in the cerebrospinal fluid-in a small preliminary study that compares patients with ALS with household controls. We suggest that environmentally driven microbiome-brain interactions may modulate ALS in mice, and we call for similar investigations in the human form of the disease.
View details for DOI 10.1038/s41586-019-1443-5
View details for PubMedID 31330533
Stromal CD38 regulates outgrowth of primary melanoma and generation of spontaneous metastasis.
2018; 9 (61): 31797–811
The outgrowth of primary melanoma, the deadliest skin cancer, and generation of metastasis is supported by the tumor microenvironment (TME) which includes non-cancerous cells. Since the TME plays an important role in melanoma pathogenesis, its targeting is a promising therapeutic approach. Thus, it is important to identify proteins in the melanoma TME that may serve as therapeutic targets. Here we show that the nicotinamide adenine dinucleotide glycohydrolase CD38 is a suitable target for this purpose. Loss of CD38 in the TME as well as inhibition of its enzymatic activity restrained outgrowth of primary melanoma generated by two transplantable models of melanoma, B16F10 and Ret-mCherry-sorted (RMS) melanoma cells. Pathological analysis indicated that loss of CD38 increased cell death and reduced the amount of cancer-associated fibroblasts (CAFs) and blood vessels. Importantly, in addition to inhibiting outgrowth of primary melanoma tumors, loss of CD38 also inhibited spontaneous occurrence of RMS pulmonary and brain metastasis. The underlying mechanism may involve, at least in the brain, inhibition of metastasis expansion, since loss of CD38 inhibited the outgrowth of B16F10 and RMS brain tumors that were generated by direct intracranial implantation. Collectively, our results suggest that targeting CD38 in the melanoma TME provides a new therapeutic approach for melanoma treatment.
View details for DOI 10.18632/oncotarget.25737
View details for PubMedID 30159123
View details for PubMedCentralID PMC6112753
Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection.
Science (New York, N.Y.)
2018; 359 (6382): 1376–83
Obesity, diabetes, and related manifestations are associated with an enhanced, but poorly understood, risk for mucosal infection and systemic inflammation. Here, we show in mouse models of obesity and diabetes that hyperglycemia drives intestinal barrier permeability, through GLUT2-dependent transcriptional reprogramming of intestinal epithelial cells and alteration of tight and adherence junction integrity. Consequently, hyperglycemia-mediated barrier disruption leads to systemic influx of microbial products and enhanced dissemination of enteric infection. Treatment of hyperglycemia, intestinal epithelial-specific GLUT2 deletion, or inhibition of glucose metabolism restores barrier function and bacterial containment. In humans, systemic influx of intestinal microbiome products correlates with individualized glycemic control, indicated by glycated hemoglobin levels. Together, our results mechanistically link hyperglycemia and intestinal barrier function with systemic infectious and inflammatory consequences of obesity and diabetes.
View details for DOI 10.1126/science.aar3318
View details for PubMedID 29519916
Our Gut Microbiome: The Evolving Inner Self.
2017; 171 (7): 1481–93
The "holobiont" concept, defined as the collective contribution of the eukaryotic and prokaryotic counterparts to the multicellular organism, introduces a complex definition of individuality enabling a new comprehensive view of human evolution and personalized characteristics. Here, we provide snapshots of the evolving microbial-host associations and relations during distinct milestones across the lifespan of a human being. We discuss the current knowledge of biological symbiosis between the microbiome and its host and portray the challenges in understanding these interactions and their potential effects on human physiology, including microbiome-nervous system inter-relationship and its relevance to human variation and individuality.
View details for DOI 10.1016/j.cell.2017.11.024
View details for PubMedID 29245010
The gut microbiome and hypertension.
Current opinion in nephrology and hypertension
2017; 26 (1): 1–8
The mammalian mucosal surfaces are densely inhabited by a diverse microbial ecosystem termed the microbiota. Among these highly heterogeneous populations, the largest and richest is the gut microbiota, recently suggested to affect various physiological traits and susceptibility to disease. Novel metagenomic and metabolomic approaches, which have been developed in the past decade, have enabled the elucidation of the contribution of the microbiota to metabolic, immunologic, neurologic and endocrine homeostasis.Dysbiosis, the alteration in the gut microbiota composition and function, has been lately associated with the pathogenesis of multifactorial diseases such as obesity, diabetes and cardiovascular disorders. Recent studies have also suggested associations between dysbiosis and essential hypertension, a common chronic medical condition affecting 20% or more of the adult population worldwide, which is considered a major causative factor for heart disease, stroke, chronic renal failure, blindness and dementia.In this review, we discuss the accumulating research pointing to possible interplays between the gut microbiome and hypertension and highlight future prospects by which utilization of microbiome-related techniques may be incorporated into the diagnosis and therapeutic arsenal of hypertension management.
View details for DOI 10.1097/MNH.0000000000000293
View details for PubMedID 27798455
Microbiome, metabolites and host immunity.
Current opinion in microbiology
2017; 35: 8–15
In the intestine, the microbial genomes and repertoire of biochemical reactions outnumber those of the host and significantly contribute to many aspects of the host's health, including metabolism, immunity, development and behavior, while microbial community imbalance is associated with disease. The crosstalk between the host and its microbiome occurs in part through the secretion of metabolites, which have a profound effect on host physiology. The immune system constantly scans the intestinal microenvironment for information regarding the metabolic state of the microbiota as well as the colonization status. Recent studies have uncovered a major role for microbial metabolites in the regulation of the immune system. In this review, we summarize the central findings of how microbiota-modulated metabolites control immune development and activity.
View details for DOI 10.1016/j.mib.2016.10.003
View details for PubMedID 27883933
Microbiome-Modulated Metabolites at the Interface of Host Immunity.
Journal of immunology (Baltimore, Md. : 1950)
2017; 198 (2): 572–80
The mammalian gastrointestinal tract and associated mucosal immune system harbor a large repertoire of metabolites of prokaryotic and eukaryotic origin that play important roles in eukaryotic development and physiology. These often bioactive small molecules originate from nutrition- and environmental-related sources, or are endogenously produced and modulated by the host and its microbiota. A complex network of interactions exists between the intestinal mucosal immune system and the microbiota. This intimate cross-talk may be driven by metabolite secretion and signaling, and features profound influences on host immunity and physiology, including the endocrine, metabolic, and nervous system function in health and disease. Alterations in microbiome-associated metabolite levels and activity are implicated in the pathogenesis of a growing number of illnesses. In this review we discuss the origin and influence of microbiome-modulated metabolites, with an emphasis on immune cell development and function. We further highlight the emerging data potentially implicating metabolite misbalance with host-microbiome-associated disease.
View details for DOI 10.4049/jimmunol.1601247
View details for PubMedID 28069752
Incipient Melanoma Brain Metastases Instigate Astrogliosis and Neuroinflammation.
2016; 76 (15): 4359–71
Malignant melanoma is the deadliest of skin cancers. Melanoma frequently metastasizes to the brain, resulting in dismal survival. Nevertheless, mechanisms that govern early metastatic growth and the interactions of disseminated metastatic cells with the brain microenvironment are largely unknown. To study the hallmarks of brain metastatic niche formation, we established a transplantable model of spontaneous melanoma brain metastasis in immunocompetent mice and developed molecular tools for quantitative detection of brain micrometastases. Here we demonstrate that micrometastases are associated with instigation of astrogliosis, neuroinflammation, and hyperpermeability of the blood-brain barrier. Furthermore, we show a functional role for astrocytes in facilitating initial growth of melanoma cells. Our findings suggest that astrogliosis, physiologically instigated as a brain tissue damage response, is hijacked by tumor cells to support metastatic growth. Studying spontaneous melanoma brain metastasis in a clinically relevant setting is the key to developing therapeutic approaches that may prevent brain metastatic relapse. Cancer Res; 76(15); 4359-71. ©2016 AACR.
View details for DOI 10.1158/0008-5472.CAN-16-0485
View details for PubMedID 27261506
Targeting CD38 in the tumor microenvironment: a novel approach to treat glioma
Cancer Cell & Microenvironment
View details for DOI 10.14800/ccm.486
Inhibition of glioma progression by a newly discovered CD38 inhibitor.
International journal of cancer
2015; 136 (6): 1422–33
Glioma, the most common cancer of the central nervous system, has very poor prognosis and no effective treatment. It has been shown that activated microglia/macrophages in the glioma tumor microenvironment support progression. Hence, inhibition of the supporting effect of these cells may constitute a useful therapeutic approach. Recently, using a syngeneic mouse glioma progression model, we showed that the ectoenzyme CD38 regulated microglia activation and, in addition, that the loss of CD38 from the tumor microenvironment attenuated glioma progression and prolonged the life span of the tumor-bearing mice. These studies, which employed wild-type (WT) and Cd38(-/-) C57BL/6J mice, suggest that inhibition of CD38 in glioma microenvironment may be used as a new therapeutic approach to treat glioma. Our study tested this hypothesis. Initially, we found that the natural anthranoid, 4,5-dihydroxyanthraquinone-2-carboxylic acid (rhein), and its highly water-soluble tri-potassium salt form (K-rhein) are inhibitors of CD38 enzymatic (nicotinamide adenine dinucleotide glycohydrolase) activity (IC50 = 1.24 and 0.84 μM, respectively, for recombinant mouse CD38). Treatment of WT, but not Cd38(-/-) microglia with rhein and K-rhein inhibited microglia activation features known to be regulated by CD38 (lipopolysaccharide/IFN-γ-induced activation, induced cell death and NO production). Furthermore, nasal administration of K-rhein into WT, but not Cd38(-/-) C57BL/6J, mice intracranially injected with GL261 cells substantially and significantly inhibited glioma progression. Hence, these results serve as a proof of concept, demonstrating that targeting CD38 at the tumor microenvironment by small-molecule inhibitors of CD38, for example, K-rhein, may serve as a useful therapeutic approach to treat glioma.
View details for DOI 10.1002/ijc.29095
View details for PubMedID 25053177
Exploring the Effects of Glycosylation and Etherification of the Side Chains of the Anticancer Drug Mitoxantrone.
2015; 10 (9): 1528–38
Herein we report the synthesis and biological evaluation of symmetric and asymmetric analogues of the DNA intercalating drug mitoxantrone (MTX) in which the side chains of the parent drug were modified through glycosylation or methyl etherification. Several analogues with glycosylated side chains exhibited higher DNA affinity than the parent MTX. The most potent in vitro cytotoxicity was observed for MTX analogue 8 (1,4-dimethoxy-5,8-bis[2-(2-methoxyethylamino)ethylamino]anthracene-9,10-dione) with methoxy ether containing side chains. Treatment of melanoma-bearing mice with MTX or analogue 8 decreased the intraperitoneal tumor burden relative to untreated mice; the effect of 8 was less pronounced than that of MTX. In vitro metabolism assays of MTX with rabbit liver S9 fraction gave rise to several metabolites; almost no metabolites were detected for MTX analogue 8. The results presented indicate that derivatization of the MTX side chain primary hydroxy groups may result in a significant improvement in DNA affinity and lower susceptibility to the formation of potentially toxic metabolites.
View details for DOI 10.1002/cmdc.201500274
View details for PubMedID 26235383
Alzheimer's disease pathology is attenuated in a CD38-deficient mouse model.
Annals of neurology
2015; 78 (1): 88–103
Alzheimer's disease (AD)-associated dementia is due to tissue damage caused by amyloid β (Aβ) deposition within the brain and by accompanying neuroinflammation. The nicotinamide adenine dinucleotide (NAD) glycohydrolase CD38, which is expressed by neurons, astrocytes, and microglial cells, regulates inflammatory and repair processes in the brain and other tissues by degrading NAD and repressing the activity of other NAD-consuming enzymes and by producing NAD-derived metabolites that regulate calcium signaling and migration of inflammatory cells. Given the role of CD38 in neuroinflammation and repair, we examined the effect of CD38 deletion on AD pathology.We crossed APPswePS1ΔE9 (APP.PS) mice with Cd38(-) (/) (-) mice to generate AD-prone CD38-deficient animals (APP.PS.Cd38(-) (/) (-) ) and examined AD-related phenotypes in both groups.APP.PS.Cd38(-) (/) (-) mice exhibited significant reductions in Aβ plaque load and soluble Aβ levels compared to APP.PS mice, and this correlated with improved spatial learning. Although CD38 deficiency resulted in decreased microglia/macrophage (MM) accumulation, the transcription profile of the Cd38(-) (/) (-) and Cd38(+/) (+) MM was similar, suggesting that the decreased Aβ burden in APP.PS.Cd38(-) (/) (-) mice was not due to alterations in MM activation/function. Instead, APP.PS.Cd38(-) (/) (-) neuronal cultures secreted less Aβ and this reduction was mimicked when APP.PS neuronal cultures were treated with inhibitors that blocked CD38 enzyme activity or the signaling pathways controlled by CD38-derived metabolites. Furthermore, β- and γ-secretase activity was decreased in APP.PS.Cd38(-) (/) (-) mice, which correlated with decreased Aβ production.CD38 regulates AD pathology in the APP.PS model of AD, suggesting that CD38 may be a novel target for AD treatment.
View details for DOI 10.1002/ana.24425
View details for PubMedID 25893674
Therapeutic effect of farnesylthiosalicylic acid on adjuvant-induced arthritis through suppressed release of inflammatory cytokines.
Clinical and experimental immunology
2014; 175 (3): 458–67
Rheumatoid arthritis (RA) is an autoimmune disease characterized by pronounced inflammation and leucocyte infiltration in affected joints. Despite significant therapeutic advances, a new targeted approach is needed. Our objective in this work was to investigate the anti-inflammatory effects of the Ras inhibitor farnesylthiosalicylic acid (FTS) on adjuvant-induced arthritis (AIA) in rats, an experimental model for RA. Following AIA induction in Lewis rats by intradermal injection of heat-killed Mycobacterium tuberculosis, rats were treated with either FTS or dexamethasone and assessed daily for paw swelling. Joints were imaged by magnetic resonance imaging and computerized tomography and analysed histologically. The anti-inflammatory effect of FTS was assessed by serum assay of multiple cytokines. After adjuvant injection rats demonstrated paw swelling, leucocyte infiltration, cytokine secretion and activation of Ras-effector pathways. Upon FTS treatment these changes reverted almost to normal. Histopathological analysis revealed that the synovial hyperplasia and leucocyte infiltration observed in the arthritic rats were alleviated by FTS. Periarticular bony erosions were averted. Efficacy of FTS treatment was also demonstrated by inhibition of CD4(+) and CD8(+) T cell proliferation and of interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-17 release. The Ras effectors PI3K, protein kinase B (AKT), p38, and extracellular-regulated kinase (ERK) were significantly attenuated and forkhead box protein 3 (FoxP3) transcription factor, a marker of regulatory T cells, was significantly increased. Thus, FTS possesses significant anti-inflammatory and anti-arthritic properties and accordingly shows promise as a potential therapeutic agent for RA. Its effects are apparently mediated, at least in part, by a decrease in proinflammatory cytokines.
View details for DOI 10.1111/cei.12235
View details for PubMedID 24215151
View details for PubMedCentralID PMC3927906
CD38 deficiency in the tumor microenvironment attenuates glioma progression and modulates features of tumor-associated microglia/macrophages.
2012; 14 (8): 1037–49
Gliomas are the most frequent primary tumors of the brain, and for highly malignant gliomas there is no successful treatment. The tumor microenvironment contains large numbers of infiltrating microglia and macrophages (MM). There is increasing evidence that the tumor-associated MM support glioma expansion. CD38 is a multifunctional ectoenzyme that uses nicotinamide adenine dinucleotide as a substrate to generate second messengers. Previously we showed that CD38 deficiency modulates microglial "activation" and impaired recovery from head trauma by a microglia-associated mechanism. In view of the supportive role of MM in glioma progression and the role of CD38 in microglia activation, we hypothesize that deficiency of CD38 in the tumor microenvironment would inhibit glioma progression. Using the syngeneic GL261 model of glioma progression in wild-type and CD38 null mice, we show here that CD38 deficiency significantly attenuates glioma expansion and prolongs the life span of the glioma-bearing mice. The CD38 deficiency effect was associated with increased cell death and decreased metalloproteinase-12 expression in the tumor mass, as well as modulation of the tumor-induced MM properties, as indicated by a reduction in the expression of the MM marker F4/80 and matrix metalloproteinases. Our results thus suggest that CD38 participates in the tumor-supporting action of MM and that targeting CD38 might be a potential therapeutic approach for glioma treatment.
View details for DOI 10.1093/neuonc/nos121
View details for PubMedID 22700727
View details for PubMedCentralID PMC3408254
Regulation of stress-induced nuclear protein redistribution: a new function of Bax and Bak uncoupled from Bcl-x(L).
Cell death and differentiation
2010; 17 (2): 346–59
Apoptosis is regulated by changes in the subcellular distribution of pro- and anti-apoptotic proteins, among which are nuclear proteins such as histone H1 (H1) and nucleophosmin (NPM). These proteins were reported to translocate to the cytosol and mitochondria, and to facilitate apoptosis in response to apoptotic stressors. The significance of this stress-induced, nuclear protein redistribution and its exact molecular mechanism are poorly understood. We show here that in mouse embryonic fibroblasts (MEFs), different apoptotic stimuli induce H1, NPM and nucleolin, but not KAP-1 nuclear/cytoplasmic redistribution, which precedes the appearance of apoptotic features. Using MEFs deficient in Bax/Bak, Apaf-1 or caspase-9, as well as caspase inhibitors, we show that this redistribution requires Bax and Bak, but neither the apoptosome nor caspases. Furthermore, the BH3 mimetic ABT-737, which acts through Bax/Bak, also stimulates nuclear protein redistribution in a Bax/Bak-dependent manner. Re-expression of Bax or Bak in Bax/Bak-deficient MEFs restores nuclear redistribution during apoptosis. This is not accompanied by Bax or Bak N-terminus exposure and is not inhibited by Bcl-x(L) overexpression. These results identify, for the first time, a function of Bax/Bak that is insensitive to inhibition by Bcl-x(L) and most likely unrelated to their canonical, pore-forming activity on mitochondria.
View details for DOI 10.1038/cdd.2009.145
View details for PubMedID 19816507