Friday, April 4, 2025
4/4/2025
Leukotriene B4 and IL-8 in alpha-1 heterozygotes (PI*MZ genotype) - Project Summary/Abstract: The purpose of this K23 Career Development Award is to develop Vickram Tejwani, MD as an independent investigator with a focus of translational investigation in heterogeneity of disease among alpha-1 heterozygotes. Dr. Tejwani has shown great promise as a young investigator and this proposal builds on his early experience with additional training in genomic and primary prospective recruitment of study participants, as well transcriptional analysis. This grant will allow hands-on experience enrolling participants, obtaining biospecimens and wet lab processing, as well as genomic and transcriptional analysis of existing datasets. This experience will be supplemented with structured coursework focused on genomic and transcriptional analytic techniques and in aggregate, will accelerate development of an independent career path. Dr. Tejwani will benefit from a multidisciplinary team of mentors, including Dr. James K. Stoller, a world authority on alpha-1 antitrypsin deficiency, Drs. Joe Zein and Victor Ortega, experts in genomic analyses and particularly the SERPINA1 gene which encodes for the alpha-1 antitrypsin protein, and Dr. Mitchell A. Olman, who will provide wet lab mentorship and resources. In aggregate, this mentorship team and institutional commitment to his research career will provide Dr. Tejwani the multidisciplinary training and guidance to develop into an independent investigator. Chronic obstructive pulmonary disease (COPD) is a highly variable disease with limited therapies, in part given prior studies do not account for disease heterogeneity with differential therapeutic responses. A deficiency of alpha-1 antitrypsin (AAT), the protein encoded for by the SERPINA1 gene, remains the best described COPD endotype. However, the heterozygous state with one wild-type allele (M) and one Z variant allele (rs28929474), known as PI*MZ, is an understudied and highly prevalent potential phenotype (affecting more than 35,000,000 globally). Epidemiologic studies demonstrate PI*MZ individuals have a wide array of disease burden among PI*MZ individuals and there is very little understanding of biologic correlates that might uniquely contribute to or be associated with disease development. Dr. Tejwani’s proposal addresses this gap through a multiomics approach with single center recruitment strengthened by analysis of existing biospecimens and genomic data from multicenter studies. He proposes to assess airway leukotriene B4 and interleukin-8 and its association with baseline disease severity, as well as longitudinal outcomes. He will also conduct for the first time, a gene-gene interaction, to see if variants in genes encoding for leukotriene B4- and interleukin-8-related genes are associated with COPD in those alpha-1 heterozygotes. Results from this study will generate preliminary data to compete for an R01-level award to conduct a trial of leukotriene- or IL-8- modifying agents on respiratory health among PI*MZ individuals utilizing leukotriene B4 and interleukin-8 airway inflammation or genotypic variants as inclusion criteria or effect modifiers.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).