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Angelo D’Alessandro

@dalessandrolab.bsky.social
628 followers 101 following 134 posts

Small molecules, big data and something (often red blood cells) in between…

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Angelo D’Alessandro @dalessandrolab.bsky.social · 10/10/2026
@aabbupdates.bsky.social @isbt.bsky.social @cuanschutz.bsky.social
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Angelo D’Alessandro @dalessandrolab.bsky.social · 10/10/2026
Thanks to Dr Karafin for a pilot clinical trial in sickle cell disease (!), Haiman and Palsson lab for modeling in mice & humans. Above all, to talented young scientists Issaian, Bevers, Marsh & Schlimgen for the extraordinary biochemistry & biophysics. This truly took a village!
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Angelo D’Alessandro @dalessandrolab.bsky.social · 10/10/2026
So much gratitude to the Janetzko lab and a stellar team of cryo-EM experts teaching us how to do this right; the Zimring lab for novel humanized mice; the REDS RBC-Omics group for an extraordinary transfusion study; and Buehler and Kao for remarkable in vivo imaging.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 10/10/2026
The variants have distinct molecular vulnerabilities, affecting red cell storage, clearance and hemolysis differently. This heterogeneity matters for the efficacy of blood transfusion - the single most common lifesaving in hospital medical procedure after vaccination
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Angelo D’Alessandro @dalessandrolab.bsky.social · 10/10/2026
We focused on 2 of the most common variants, African A− and Mediterranean G6PD, combining four new cryo-EM structures, novel humanized mouse models, deep multi-omics of >13,000 donors, and clinical transfusion studies - including a pilot trial in sickle cell disease.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 10/10/2026
G6PD catalyzes the rate-limiting step of the pentose phosphate pathway, central to cancer, aging, cardiovascular disease and exercise physiology. Over 230 variants are known, yet remarkably little is understood about their structural and functional heterogeneity.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 10/10/2026
500 million people - 6% of humanity -are G6PD deficient. G6PD is key to cancer, aging & exercise, but >230 variants remain poorly understood. New preprint: “Structural divergence of G6PD variants shapes red blood cell storage and transfusion performance” www.biorxiv.org/content/10.1...
biorxiv.org
Structural divergence of G6PD variants shapes red blood cell storage and transfusion performance
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy, yet how donor alleles shape red blood cell (RBC) storage, transfusion performance, and recipient physiology remains ...
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Angelo D’Alessandro @dalessandrolab.bsky.social · 02/06/2026
Now out in Blood @ash.hematology.org @bloodjournals.hematology.org ashpublications.org/blood/articl... Really proud of this one, and grateful to the reviewers for the constructive criticism. It really is a much better paper now!
ashpublications.org
The red blood cell proteome and interactome identify a Band 3-BLVRB axis regulating hypoxic metabolic adaptation
Key Points. Deep proteomics defines a complete, contamination-free RBC proteome (3,775 proteins) and O2-dependent interactome by Xlinking proteomicsThe Ban
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Angelo D’Alessandro @dalessandrolab.bsky.social · 03/05/2026
Congratulations!
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Reposted by Angelo D’Alessandro
Shicheng Guo @shihcheng.bsky.social · 24/03/2026
New study reveals POCA method for dual protein & lipid interactome mapping using a single singlet oxygen photosensitizer! PMID:41652064, Nat Chem Biol 2026, @nchembio doi.org/10.1038/s41589-026-02140-1 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪
doi.org
Photosensitizer proximity labeling captures the lipid and protein interactomes | Nature Chemical Biology
The physical properties of cellular membranes are influenced by protein and lipid interactions. In situ proximity labeling interactomic methods are well suited to characterize these dynamic and often fleeting interactions. Yet, available methods require distinct chemistries for proteins and lipids. Here we establish a singlet oxygen-based photocatalytic proximity labeling platform (POCA) that reports intracellular interactomes for both proteins and lipids using cell-penetrant photosensitizer reagents. Cholesterol-directed POCA captured known and unprecedented cholesterol-binding proteins, including protein complexes sensitive to intracellular cholesterol levels and proteins uniquely captured by physiologically relevant lipoprotein uptake. Protein-directed POCA accurately mapped intracellular membrane complexes, defined sterol-dependent changes to the interactome of the cholesterol transport protein Aster-B and revealed singlet oxygen-mediated domain-specific Aster crosslinking. More br
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
Disclosure: some of the thinking behind this paper -including the donor label “Super Agers” (ΔAge = predicted – chronological age < −15 years) - was inspired by the work and writing of @erictopol.bsky.social, whose book I happened to be reading while developing this story
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
As always, this work involved a whole village of friends and colleagues at: Vitalant @cuanschutz.bsky.social @columbiauniversity.bsky.social @ubcpress.bsky.social @uvapress.bsky.social @ucsfhealth.bsky.social Special thanks to NHLBI @aabbupdates.bsky.social for their continued support
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
Large-scale RBC omics may enable: • precision transfusion medicine • biomarkers of systemic and organ-specific aging • population-scale monitoring of metabolic health
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
Conceptually, this supports a broader idea: Red blood cells are not just oxygen carriers, rather they are circulating reporters of systemic metabolic health.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
The story goes beyond transfusion medicine. RBC aging-clock omics signatures are also linked to brain iron, myelin-related phenotypes, and neurocognitive test performance.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
This suggests RBC omics captures stable biological features of donors, bridging: genetics → cellular physiology → clinical blood product quality → population-scale donor biology.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
Even more interesting: RBC aging signatures also predict future donor behavior - including long-term donation trajectories >12 years later.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
Importantly, this is not irreversible. In donors repleted with IV iron dextran, the RBC aging signal is reset toward a younger state — supporting a direct link between systemic iron biology and RBC molecular age.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
The clock is also informative in healthy donors. High-frequency donors tend to show signatures of slower biological RBC aging. But that advantage is not unconditional: when frequent donation leads to iron depletion, RBC biological aging appears to accelerate.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
By studying orthogonal cohorts of >1k patients, we found that accelerated RBC aging is not random. It tracks with hemolysis-related biology, including conditions such as G6PD deficiency, sickle cell trait, and sickle cell disease, which shift RBCs toward an older biological state
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
Deviation between predicted and chronological age (ΔAge) correlates with RBC storage quality and hemolysis susceptibility, linking aging signatures to transfusion-relevant phenotypes, including post-transfusion boost in >10k recipient hemoglobin levels.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
Age acceleration was associated with certain genetic traits linked to inflammation and ECM remodeling, but also by blood donor BMI, sex and ethnicity.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
Using machine learning, we leveraged these protein signatures to build RBC aging clocks. These clocks predict chronological age from RBC proteomes, but also reveal individuals whose RBC biology appears “older” or “younger” than expected.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
We found that RBC protein abundance is highly structured by genetics. Many proteins show strong protein quantitative trait loci (pQTLs), revealing that the RBC proteome is partly hard-wired in the genome.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
Obese and morbidly obese donors show elevated circulating markers of inflammation - including complement and coagulation components - linked to accelerated aging. Ethnicity also plays a role, suggesting that genetic traits may impact RBC proteomes (e.g., G6PD status).
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
Biological sex shows sexually dimorphic omics trajectories, with converging clusters after 51, the average age for menopause in the United States
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
RBC proteins and metabolites clustered along aging trajectories, linked to inflammation (complement and coagulation cascades) and antioxidant capacity (glutathione homeostasis, pentose phosphate pathway)
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
To address this, we profiled the RBC proteome and metabolome in >13,000 blood donors from the REDS-III RBC-Omics cohort, also genotyped at >800k SNPs. This generated one of the largest multi-omics resources ever produced for a circulating human cell.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
But despite transfusing ~110+ million units annually worldwide, we still know surprisingly little about: • the full RBC proteome at population scale • how genetics shapes RBC biology • whether RBC molecular signatures predict transfusion outcomes
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
Red blood cells (RBCs) circulate for ~120 days and continuously exchange metabolites with every organ. This makes them a unique integrative biosensor of systemic physiology — capturing genetics, metabolism, environment, and lifestyle (the "exposome").
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
In our new preprint, we built a population-scale red blood cell proteome atlas across >13,000 blood donors and discovered genetically encoded aging clocks that predict RBC quality and donor trajectories. www.biorxiv.org/content/10.6...
biorxiv.org
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Angelo D’Alessandro @dalessandrolab.bsky.social · 09/03/2026
Blood offers a window on systemic metabolic health — a founding principle of clinical biochemistry. How much information about human aging is encoded in a drop of blood? Profiling the RBC proteome in >13,000 donors reveals genetically encoded aging clocks predicting RBC quality
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Angelo D’Alessandro @dalessandrolab.bsky.social · 23/02/2026
@ishahjain.bsky.social sorry! Forgot to tag
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Angelo D’Alessandro @dalessandrolab.bsky.social · 22/02/2026
RBCs are not passive bystanders in systems metabolism. We had been saying this for years. This time, in collaboration with Isha Jain @gladstoneinst.bsky.social By the way, the Jain lab is on a roll, with ever more elegant science at each paper. It was a pleasure to collaborate!
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Reposted by Angelo D’Alessandro
Gladstone Institutes @gladstoneinst.bsky.social · 19/02/2026
New study shows red blood cells act as hidden glucose sponges in low-oxygen conditions, explaining why people living at high altitude have lower diabetes rates. @dalessandrolab.bsky.social @medschool.umaryland.edu @cp-cellmetabolism.bsky.social @arcinstitute.org @ishahjain.bsky.social
bit.ly
Red Blood Cells Soak Up Sugar at High Altitude, Protecting Against Diabetes
New study shows red blood cells act as hidden glucose sponges in low-oxygen conditions, explaining why people living at high altitude have lower diabetes rates and pointing toward new treatments.
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Reposted by Angelo D’Alessandro
Lab on a Chip @labonachip.rsc.org · 08/01/2026
On the outside back cover of issue 1 of Lab on a Chip: Surface acoustic wave hemolysis assay for evaluating stored red blood cells. #OpenAccess from Angelo D'Alessandro, Xiaoyun Ding et al @dalessandrolab.bsky.social @cuanschutz.bsky.social @colorado.edu Read now: pubs.rsc.org/en/content/a...
Outside back cover of issue 1 of Lab on a Chip: Five channels of lysing blood cells leading to humanoid silhouettes
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Reposted by Angelo D’Alessandro
International Society of Blood Transfusion @isbt.bsky.social · 19/12/2025
Cracking the code of blood: How genetics and metabolism are transforming transfusions 🔗 Read the full Transfusion Today article here: isbtweb.foleon.com/transfusion-toda… #TransfusionMedicine #ISBT #TransfusionToday
isbtweb.foleon.com
Cracking the Code of Blood - Transfusion Today - October 2025
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Reposted by Angelo D’Alessandro
Galligan Lab @galliganlab.bsky.social · 18/12/2025
www.jbc.org/article/S002...
jbc.org
Glyoxalase 1 is a proadipogenic gene
Diabetes is one of the most prevalent and widespread diseases, with the majority of cases stemming from prolonged obesity. Obesity occurs through the expansion of adipose tissue in an unhealthy and dy...
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Reposted by Angelo D’Alessandro
Vijay G. Sankaran @bloodgenes.bsky.social · 18/12/2025
Terrific to have our paper, led by @tjflemin.bsky.social, featured as a plenary article in @bloodjournal.bsky.social today: ashpublications.org/blood/articl...
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Reposted by Angelo D’Alessandro
Christian Frezza @frezzalab.bsky.social · 18/12/2025
link.springer.com/article/10.1... The transaminase-ω-amidase pathway senses oxidative stress to control glutamine metabolism and α-ketoglutarate levels in endothelial cells
link.springer.com
The transaminase-ω-amidase pathway senses oxidative stress to control glutamine metabolism and α-ketoglutarate levels in endothelial cells - The EMBO Journal
Oxidative stress is a major driver of cardiovascular disease; however, the fast changes in cellular metabolism caused by short-lived reactive oxygen species (ROS) remain ill-defined. Here, we characte...
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Angelo D’Alessandro @dalessandrolab.bsky.social · 10/12/2025
Congrats to Sweta and to you, Eric!
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Reposted by Angelo D’Alessandro
Nature Metabolism @natmetabolism.nature.com · 03/12/2025
bit.ly
Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy
Nature Metabolism, Published online: 03 December 2025; doi:10.1038/s42255-025-01412-9Chaperone-mediated autophagy declines with age in skeletal muscle of humans and mice, leading to muscle dysfunction characterized by impaired calcium homoeostasis and mitochondrial function.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 01/12/2025
As always, it takes a village... So grateful to the many collaborators that made this study happen, and to #NIH #NHLBI for the support #hematology #RBC #RedBloodCell #Erythrocyte #Hypoxia #Exercise #Physiology @cuanschutz.bsky.social
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Angelo D’Alessandro @dalessandrolab.bsky.social · 01/12/2025
Similar mechanisms exists in plants: under hypoxia-like conditions (high CO₂/low O₂), NO levels rise and S-nitrosate GAPDH at C152, transiently modulating its activity and redirecting carbon flux like in RBCs! This parallel highlights a conserved NO-relay logic tuning metabolism across kingdoms
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Angelo D’Alessandro @dalessandrolab.bsky.social · 01/12/2025
Together, the data outline a Band 3–BLVRB–hemoglobin network that links oxygen sensing, redox chemistry, and metabolic adaptation in an anucleate cell.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 01/12/2025
Mechanistically, BLVRB Cys109 functions as an NO-transfer relay, modulating glycolytic enzymes such as GAPDH through S-nitrosation. This provides a redox-based feedback mechanism that tunes metabolism to oxygen availability.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 01/12/2025
Population-scale RBC proteome-QTL analyses (13,000 donors) show coordinated variation in SLC4A1 and BLVRB abundance, supporting the presence of a conserved regulatory axis across individuals.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 01/12/2025
In humanized mice, loss of the Band 3 N-terminus disrupts glycolytic activation, lowers 2,3-BPG production, and impairs exercise tolerance, linking this molecular module to whole-organism physiology.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 01/12/2025
A key finding is that BLVRB (biliverdin reductase B) binds the Band 3 N-terminus under oxygenated conditions and dissociates under hypoxia, when Band 3–deoxyhemoglobin interactions increase. This reversible switch integrates structural, redox, and metabolic control.
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Angelo D’Alessandro @dalessandrolab.bsky.social · 01/12/2025
Despite the lack of de novo gene expression, the architecture of the human RBC proteome is oxygen responsive through ultra-structural changes. Using deep proteomics, cross-linking interactomics, structural biochemistry, and mouse models, we map how these changes are organized around Band 3 (SLC4A1).
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