About

Gabriel G. Haddad is a faculty member within the Department of Pediatrics at the University of California San Diego, which is a leading institution established in 1969 and became the primary pediatric provider for Rady Children's Hospital-San Diego in 2001. The department is dedicated to excellence in clinical care, scientific discovery, medical education, and community benefit, serving children and families across Southern California. Although the page does not specify Haddad's exact research focus or background, it highlights the department's commitment to advancing pediatric healthcare through clinical programs, research efforts spanning clinical, translational, and basic sciences, and educational opportunities for trainees. The department includes numerous divisions and over 285 faculty members, emphasizing a collaborative environment aimed at improving diagnostics, developing innovative therapies, and training the next generation of pediatric healthcare professionals. The department is engaged in cutting-edge advancements in pediatrics, including multiomics, computational biology, and artificial intelligence, which are transforming understanding and treatment of childhood diseases.

Research topics

• Biology
• Neuroscience
• Genetics
• Medicine
• Endocrinology
• Cancer research
• Pathology

Selected publications

• Gut microbiota and derived metabolites mediate obstructive sleep apnea induced atherosclerosis

  Gut Microbes · 2025-03-02 · 16 citations

  articleOpen accessSenior authorCorresponding

  mice in the aorta under HFHC/IHC conditions. In contrast, microbial colonization did not show a significant impact on the atherosclerotic progression in PA. In summary, this research demonstrated that (1) IHC acts cooperatively with HFHC to induce atherosclerosis; (2) gut microbiota modulate atherogenesis, induced by HFHC/IHC, in the aorta not in PA; (3) different analytical methods suggest that a specific imbalance between Akkermansiaceae and Muribaculaceae bacterial families mediate OSA-induced atherosclerosis; and (4) derived bile acids, such as deoxycholic acid and lithocholic acid, regulate atherosclerosis in OSA. The knowledge obtained provides novel insights into the potential therapeutic approaches to prevent and treat OSA-induced atherosclerosis.

  PublisherOA PDFDOI

• Klinefelter syndrome: A neurodevelopmental disease of the synapse

  Neurobiology of Disease · 2025-06-25

  articleOpen accessSenior authorCorresponding

  Klinefelter syndrome (KS; 47,XXY) is the most common sex chromosome disorder, affecting approximately 1 in every 500 to 650 newborn males. Children with KS display a spectrum of phenotypic manifestations, including abnormal neurocognitive phenotypes. However, due to the limited research focusing on the central nervous system, our understanding of the neurobiology of KS at the cellular and molecular levels remains largely unclear. In this study, we utilized cortical organoids derived from pluripotent stem cells and transcriptomic analysis to explore the mechanisms underlying early brain developmental defects in KS patients. We demonstrate that KS organoids display altered neurogenesis, gliogenesis, and glutamate signaling pathways. We believe these early alterations contribute to the abnormal brain development and later cognitive phenotypes in KS patients. • Klinefelter syndrome (KS) is the most common sex chromosome disorder. • Children with KS display abnormal neurocognitive phenotypes. • Cortical organoids derived from KS show atypical early brain development with altered neurogenesis, gliogenesis, and glutamate signaling pathways.

  PublisherDOI

• Integrated multiomics reveals inflammation-driven excessive erythrocytosis in subjects with Monge’s disease

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-21

  preprintSenior authorCorresponding

  Abstract Monge’s disease, or Chronic Mountain Sickness (CMS), is a chronic high-altitude disorder characterized by hypoxia-induced excessive erythrocytosis (EE), elevating the risk of stroke and myocardial infarction. Using RNA-seq and ATAC-seq, we profiled iPSC-derived erythroid cells from CMS and non-CMS subjects under normoxia and hypoxia to identify statistically significant, disease-associated transcriptional and chromatin accessibility changes. RNA-seq revealed induction of inflammatory, stress, and erythropoiesis programs in CMS even under normoxia, including robust activation of JAK/STAT signaling, upregulation of heme metabolism and VEGF, and accelerated erythrocyte lineage commitment alongside repression of Notch and WNT/β-catenin. Hypoxia amplified this dysregulated state, and critically, activated NFκB-driven inflammatory signaling together with canonical HIF targets. ATAC-seq revealed pronounced hypoxia-induced changes, with increased accessibility within inflammatory and erythrocyte lineage genes occurring concomitantly with decreased accessibility within pluripotency and ectodermal lineage genes. Pharmacological NFκB inhibition in CMS cells significantly reduced EE ( p -value <0.0001), whereas NFκB activation in non-CMS cells was sufficient to drive EE ( p -value <0.01), confirming the causal role inferred by our multiomics analyses. Collectively, our multiomics and functional experiments substantiate a coordinated chromatin–transcription paradigm favoring an inflammatory axis that, through hypoxia-driven NFκB activation, accelerates stress-induced erythroid commitment and underlies EE in CMS.

  PublisherDOI

• Author Correction: Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content

  Nature Communications · 2025-02-12

  erratumOpen access

  Correction to: Nature Communicationshttps://doi.org/10.1038/s41467-022-29942-w, published online 02 May 2022 In the version of the article initially published, the text “UCSD has filed a patent application (WO2022072709A1), in which F.P. and A.R.M. are inventors, containing some results regarding the TCF4 correction overexpression strategy described in this paper. The patent was published on 04-07-2022” was missing from the Competing interests section and has now been added to the HTML and PDF versions of the article.

  PublisherOA PDFDOI

• 1270 MICROBIAL BILE ACID BIOTRANSFORMATIONS PROMOTE ATHEROSCLEROSIS ASSOCIATED WITH OBSTRUCTIVE SLEEP APNEA

  Gastroenterology · 2024-05-01

  article
  PublisherDOI

• A Single Mutation in the SENP1 Region Regulates the Excessive Erythropoiesis in the Andes

  Blood · 2024-11-05

  articleOpen accessSenior author

  Background: Approximately 20% of individuals living in Peruvian mountains suffer from debilitating Monge's disease or Chronic Mountain Sickness (CMS). They manifest the disease in adulthood and often die because of excessive erythropoiesis (EE) (Hematocrit of >65%, averaging 72%, mostly occurring in males), an extreme phenotype that often leads to myocardial infarction or stroke. The uniqueness of this Andean population is even more significant when we realize that there are individuals who live side by side at the same altitude as those with CMS but do not suffer from the same extreme phenotype (non-CMS). We have shown a critical role of SENP1 (a gene we obtained from differential SNP analysis throughout whole genomes) in regulating EE response in the highlanders. In order to understand the mechanism(s)that upregulates SENP1 levels in CMS, we applied bioinformatics approaches and CRISPR/Cas9-mediated genomic editing to decipher causal SNPs in the SENP1 region. Methods: We performed Whole Genome Analysis and applied bioinformatics methods iSAFE (integrated Selection of Allele Favored by Evolution) and CADD (Combined Annotation Dependent Depletion) Score to identify causal SNPs in the selected region of SENP1 gene that could lead to the pathology. We further utilized an in-vitro human iPS-derived model system and CRISPR approach to switch alleles and study their functional role in regulating the EE response. Results: By applying iSAFE and CADD score we were able to shortlist 7 causal SNPs: rs10783232, rs7959755, rs17122612, rs72644843, rs11609399, rs11613781 and rs60629297. Among them, rs7959755 and rs10783232 were the top ranked (Rank 1 and 2) SNPs. We successfully generated and validated A to G switch in the rs10783232 in the non-CMS cells using CRISPR. We further tested the impact of this switch on function of the allele and observed a significant increase in SENP1 mRNA levels (p<0.05) as well doubling of BFU-e colonies (p<0.05) in the non-CMS cells as compared to the control non-CMS cells. We also tested the effect of allele switch (G to A) for the lower ranked (Rank 44) SNP rs11613781 and did not observe a significant effect on SENP1 levels or BFU colony formation. Conclusion: These results demonstrate that rs10783232 plays a critical role in regulating SENP1 mRNA levels under hypoxia as well as the EE in the Andean highlanders.

  PublisherOA PDFDOI

• Gut Microbiota and Derived Metabolites Mediate Obstructive Sleep Apnea Induced Atherosclerosis

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-11-19

  preprintOpen accessSenior authorCorresponding

  Abstract Background Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia/hypercapnia (IHC), affects predominantly obese individuals, and increases atherosclerosis risk. Since we and others have implicated gut microbiota and metabolites in atherogenesis, we dissected their contributions to OSA-induced atherosclerosis. Results Atherosclerotic lesions were compared between conventionally-reared specific pathogen free (SPF) and germ-free (GF) ApoE -/- mice following a high fat high cholesterol diet (HFHC), with and without IHC conditions. The fecal microbiota and metabolome were profiled using 16S rRNA gene amplicon sequencing and untargeted tandem mass spectrometry (LC-MS/MS) respectively. Phenotypic data showed that HFHC significantly increased atherosclerosis as compared to regular chow (RC) in both aorta and pulmonary artery (PA) of SPF mice. IHC exacerbated lesions in addition to HFHC. Differential abundance analysis of gut microbiota identified an enrichment of Akkermansiaceae and a depletion of Muribaculaceae (formerly S24-7) family members in the HFHC-IHC group. LC-MS/MS showed a dysregulation of bile acid profiles with taurocholic acid, taurodeoxycholic acid, and 12-ketodeoxycholic acid enriched in the HFHC-IHC group, long-chain N-acyl amides, and phosphatidylcholines. Interestingly, GF ApoE -/- mice markedly reduced atherosclerotic formation relative to SPF ApoE -/- mice in the aorta under HFHC/IHC conditions. In contrast, microbial colonization did not show a significant impact on the atherosclerotic progression in PA. Conclusions In summary, this research demonstrated that (1) IHC acts cooperatively with HFHC to induce atherosclerosis; (2) gut microbiota modulate atherogenesis, induced by HFHC/IHC, in the aorta not in PA; (3) different analytical methods suggest that a specific imbalance between Akkermansiaceae and Muribaculaceae bacterial families mediate OSA-induced atherosclerosis; and (4) derived bile acids, such as deoxycholic acid and lithocholic acid, regulate atherosclerosis in OSA. The knowledge obtained provides novel insights into the potential therapeutic approaches to prevent and treat OSA-induced atherosclerosis.

  PublisherOA PDFDOI

• Brain organoid protocols and limitations

  Frontiers in Cellular Neuroscience · 2024-03-20 · 38 citations

  reviewOpen accessSenior authorCorresponding

  Stem cell-derived organoid technology is a powerful tool that revolutionizes the field of biomedical research and extends the scope of our understanding of human biology and diseases. Brain organoids especially open an opportunity for human brain research and modeling many human neurological diseases, which have lagged due to the inaccessibility of human brain samples and lack of similarity with other animal models. Brain organoids can be generated through various protocols and mimic whole brain or region-specific. To provide an overview of brain organoid technology, we summarize currently available protocols and list several factors to consider before choosing protocols. We also outline the limitations of current protocols and challenges that need to be solved in future investigation of brain development and pathobiology.

  PublisherOA PDFDOI

• Investigating the neurobiology of maternal opioid use disorder and prenatal opioid exposure using brain organoid technology

  Frontiers in Cellular Neuroscience · 2024-05-15 · 9 citations

  reviewOpen accessSenior authorCorresponding

  Over the past two decades, Opioid Use Disorder (OUD) among pregnant women has become a major global public health concern. OUD has been characterized as a problematic pattern of opioid use despite adverse physical, psychological, behavioral, and or social consequences. Due to the relapsing–remitting nature of this disorder, pregnant mothers are chronically exposed to exogenous opioids, resulting in adverse neurological and neuropsychiatric outcomes. Collateral fetal exposure to opioids also precipitates severe neurodevelopmental and neurocognitive sequelae. At present, much of what is known regarding the neurobiological consequences of OUD and prenatal opioid exposure (POE) has been derived from preclinical studies in animal models and postnatal or postmortem investigations in humans. However, species-specific differences in brain development, variations in subject age/health/background, and disparities in sample collection or storage have complicated the interpretation of findings produced by these explorations. The ethical or logistical inaccessibility of human fetal brain tissue has also limited direct examinations of prenatal drug effects. To circumvent these confounding factors, recent groups have begun employing induced pluripotent stem cell (iPSC)-derived brain organoid technology, which provides access to key aspects of cellular and molecular brain development, structure, and function in vitro . In this review, we endeavor to encapsulate the advancements in brain organoid culture that have enabled scientists to model and dissect the neural underpinnings and effects of OUD and POE. We hope not only to emphasize the utility of brain organoids for investigating these conditions, but also to highlight opportunities for further technical and conceptual progress. Although the application of brain organoids to this critical field of research is still in its nascent stages, understanding the neurobiology of OUD and POE via this modality will provide critical insights for improving maternal and fetal outcomes.

  PublisherOA PDFDOI

• Cholesterol, not fat, is critical in atherogenesis induced by intermittent hypoxia and hypercapnia

  Physiology · 2023-05-01 · 1 citations

  articleSenior author

  Obstructive sleep apnea (OSA) is a prevalent sleep disorder characterized by intermittent hypoxia and hypercapnia (IHC) and is known to increase risk for atherosclerosis. Most of OSA patients are obese. However, the particular role of high fat and high cholesterol in inducing or promoting atherosclerosis under IHC remains obscure. To dissect the mechanisms involved, we examined atherosclerotic formation in the Aorta, Aortic arch and Pulmonary artery (PA) in pro-atherogenesis mouse model, the apolipoprotein E ( ApoE) deficient mice, after IHC exposure on either high fat diet (HF, 60% fat by Kcal and 0.003% cholesterol by weight) or high fat high cholesterol diet (HFHC, 42% fat by Kcal and 1.3% cholesterol by weight), and compared them to room air (RA) control groups fed with HF, HFHC or regular chow (RC, 10% fat by Kcal and 0.003% cholesterol by weight). Our data revealed that HFHC-treated mice had significantly more atherosclerotic lesions than those fed with RC in room air (e.g. Aorta, RA-HFHC 8.1±0.76% vs RA-RC 1.0±0.27%, p<0.01). 10-week IHC treatment further accelerated atherogenesis in Aorta, Aortic arch and PA as compared to RA controls in the presence of HFHC (Aorta, IHC-HFHC 13.8±0.96% vs RA-HFHC 8.1±0.76%, p<0.01; Aortic arch, IHC-HFHC 28.5±1.88% vs RA-HFHC 16.6±2.00%, p<0.01; PA, IHC-HFHC 28.9±2.81% vs RA-HFHC 12.2±1.51%, p<0.01). Intriguingly, HF diet alone didn’t cause significant difference in terms of atherosclerotic lesions among RA-RC, Air-HF and IHC-HF groups (Aorta, IHC-HF 0.6±0.20% vs RA-HF 0.1±0.06% vs RA-RC 0.4±0.08%, p>0.01; Aortic arch, IHC-HF 2.0±0.73% vs RA-HF 0.4±0.20% vs RA-RC 1.0±0.26%, p>0.01; and PA, IHC-HF 1.4±0.33% vs RA-HF 0.2±0.20% vs RA-RC 0.0±0.04%, p>0.01), indicating that high fat alone is insufficient to induce atherosclerosis under both RA and IHC conditions. In conclusion, our data demonstrated that (1) high cholesterol, but not high fat, plays a critical role in the development of atherosclerosis; (2) impact of IHC on atherosclerosis depends on the presence of HFHC. This study is supported by the National Institutes of Health grant 1R01HL157445-01A1. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

  PublisherDOI

Recent grants

• NIH Grant R01NS037756

  NIH · $4.1M · 2011

• NIH Grant P01HD032573

  NIH · $23.2M · 2011

• NIH Grant R01NS035918

  NIH · $944k · 2000

• Effect of methadone on the developmental properties of human brain organoids

  NIH · $3.2M · 2022–2027

• Training in Translational Lung Biology and Pathobiology

  NIH · $14.8M · 1994–2026

Frequent coauthors

• Dan Zhou

  Sichuan University

  120 shared

• Hang Yao

  Binzhou University

  55 shared

• Jin Xue

  Hunan Agricultural University

  54 shared

• Robert M. Douglas

  University of British Columbia

  48 shared

• Orit Poulsen

  University of California, San Diego

  46 shared

• Priti Azad

  University of California, San Diego

  43 shared

• Tsering Stobdan

  University of California, San Diego

  30 shared

• Julie Ryu

  29 shared