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Alagpulinsa Laboratory
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Research Projects

Investigating hematopoietic function as a conduit for genetic pleiotropy in human complex traits and diseases

Genetic variants associated with complex traits and diseases rarely act in isolation. Instead, they form interconnected networks that influence multiple phenotypes through shared molecular and cellular mechanisms, a phenomenon known as pleiotropy.

Our laboratory investigates the hematopoietic system as a unifying conduit for pleiotropy, where perturbations in hematopoietic stem cell (HSC) function reverberate across immune, metabolic, and neurocognitive domains to influence multi-trait outcomes. Throughout life, HSCs regenerate the blood and immune systems, producing over 100 billion new cells each day to sustain oxygen transport, immune defense, and systemic homeostasis. When this process becomes dysregulated, its effects ripple through virtually every organ system, positioning hematopoiesis as a central driver of disease co-occurrence and antagonism.

We focus on autoimmune diseases, particularly type 1 diabetes (T1D), and their co-occurring neurocognitive and cardiovascular traits as model systems to dissect the molecular and cellular architecture of pleiotropy. By integrating population-scale genetics, single-cell and multi-omic analyses, and translational models, we trace how pleiotropic variation within the hematopoietic system shapes health and disease across organ systems.

Our systems-level approach reframes the genetic basis of complex traits as a function of networked biology, revealing shared mechanisms that unify immunity, metabolism, and neurocognition—and illuminating new opportunities for cross-disease prevention, precision medicine, and therapeutic innovation.

Hematopoietic function as a conduit for genetic pleiotropy linking multiple traits and diseases

Selected Publications

*Denotes corresponding author; $denotes equal contribution

  1. Saarah P, Syeda ZA, Xu Z, Dong Y, Jiang A, Shanguhyia M, Roy S, Zhu B, Zhang L, Dewan AT, Asgari S, Alagpulinsa DA*. Shared genetic and neuroimmune architecture links type 1 diabetes with neurocognitive traits. medRxiv. 2025. DOI: 10.1101/2025.09.14.25335719.
  2. Adebekun J, Nadig A, Saarah P, Asgari S, Kachuri L, Alagpulinsa DA*. Genetic relations between type 1 diabetes, coronary artery disease and leukocyte counts. Diabetologia. Nov 2024;67(11):2518-2529. doi:10.1007/s00125-024-06247-9.
  3. Schnittman SR, Talathi R, Wilks MQ, Hedgire S, Lu MT, Fourman LT, Alagpulinsa DA, et al. Association of T-cell subtypes with macrophage-specific arterial infiltration in people with HIV. AIDS. Nov 15, 2024;38(14):1940-1946. doi:10.1097/qad.0000000000003967.
  4. Sremac M, Luo H, Deng H, Parr MFE, Hutcheson J, Verde PS, Alagpulinsa DA, et al. Short-term function and immune-protection of microencapsulated adult porcine islets with alginate incorporating CXCL12 in healthy and diabetic non-human primates without systemic immune suppression: A pilot study. Xenotransplantation. Nov-Dec 2023;30(6):e12826. doi:10.1111/xen.12826.
  5. Robinson JA, Toribio M, Quinaglia T, Awadalla M, Talathi R, Durbin CG, Alhallak I, Alagpulinsa DA, et al. Plasma osteopontin relates to myocardial fibrosis and steatosis and to immune activation among women with HIV. AIDS. Feb 1, 2023;37(2):305-310. doi:10.1097/qad.0000000000003417.
  6. Alagpulinsa DA*, Toribio MP, Alhallak I, Shmookler Reis RJ. Advances in understanding the molecular basis of clonal hematopoiesis. Trends in molecular medicine. Mar 25, 2022; doi: 10.1016/j.molmed.2022.03.002.
  7. Alolga RN, Opoku-Damoah Y, Alagpulinsa DA$, et al. Metabolomic and transcriptomic analyses of the anti-rheumatoid arthritis potential of xylopic acid in a bioinspired lipoprotein nanoformulation. Biomaterials. Jan 2021; 268:120482. doi: 10.1016/j.biomaterials.2020.120482.
  8. Alagpulinsa DA*, Szalat RE, Poznansky MC, Shmookler Reis RJ. Genomic Instability in Multiple Myeloma. Trends in cancer. Oct 2020;6(10):858-873. doi: 10.1016/j.trecan.2020.05.006.
  9. Alagpulinsa DA, Cao JJL, Sobell D, Poznansky MC. Harnessing CXCL12 signaling to protect and preserve functional beta-cell mass and for cell replacement in type 1 diabetes. Pharmacology & Therapeutics. Jan 2019; 193:63-74. doi: 10.1016/j.pharmthera.2018.08.011.
  10. Alagpulinsa DA, Cao JJL, Driscoll RK, et al. Alginate-microencapsulation of human stem cell-derived beta cells with CXCL12 prolongs their survival and function in immunocompetent mice without systemic immunosuppression. American Journal of Transplantation. Feb 12, 2019; doi:10.1111/ajt.15308.
  11. Alagpulinsa DA, Kumar S, Talluri S, et al. Amplification and overexpression of E2 ubiquitin conjugase UBE2T promotes homologous recombination in multiple myeloma. Blood Advances. 2019;3(23):3968-3972. doi:10.1182/bloodadvances.2019000181.
  12. Alagpulinsa DA, Ayyadevara S, Yaccoby S, Shmookler Reis RJ. A Cyclin-Dependent Kinase Inhibitor, Dinaciclib, Impairs Homologous Recombination and Sensitizes Multiple Myeloma Cells to PARP Inhibition. Molecular Cancer Therapeutics. Feb 2016;15(2):241-50. doi: 10.1158/1535-7163.mct-15-0660.
  13. Alagpulinsa DA, Yaccoby S, Ayyadevara S, Shmookler Reis RJ. A peptide nucleic acid targeting nuclear RAD51 sensitizes multiple myeloma cells to melphalan treatment. Cancer Biology & Therapy. 2015;16(6):976-86. doi:10.1080/15384047.2015.1040951.
  14. Alagpulinsa DA, Ayyadevara S, Shmookler Reis RJ. A Small-Molecule Inhibitor of RAD51 Reduces Homologous Recombination and Sensitizes Multiple Myeloma Cells to Doxorubicin. Front Oncol. 2014;4(289).
  15. Toribio M, Awadalla M, Drobni ZD, Quinaglia T, Wang M, Durbin CG, Alagpulinsa DA, et al. Cardiac strain is lower among women with HIV in relation to monocyte activation. PloS One. 2022;17(12):e0279913. doi: 10.1371/journal.pone.0279913.