Palo Alto Veterans Institute for Research

What it reported doing in 2024

Novel lymphocyte chemoattractant receptor and ligand. Principal investigator: eugene butcher, m.d.we have identified a novel lymphocyte chemoattractant receptor and its chemoattractant ligand, selectively expressed in lung, airways, upper gi tract, genitourinary mucosae and mucosa-associated glands including the pancreas and salivary glands. Aim 1: we will mechanistically probe the receptor-ligand interactions focusing on the specificity and signaling pathways activated by the novel receptor and its role as a lymphocyte vs myeloid cell chemotactic receptor. Structure-function studies will identify ligand domains for receptor binding and activation. Aim 2: will define the regulation of the receptor in the mouse, and its role in lymphocyte population of and homing to non-lymphoid tissues during homeostasis and in the setting of chronic multi-organ autoimmune inflammation. The roles of the pathway in immune cell development will be probed in mixed bone marrow chimeras in which receptor-deficient vs wild type stem cells compete for reconstitution of immune compartments in lymphoid and non-lymphoid tissues. Aim 3: will elucidate the tissue- and cell subset-specific expression of the receptor and ligand in humans.while much of aim 1 has been completed and presented in our nature publication, this aim as well as the grant as a whole has as its overarching goal to identify and characterize the gpcr interactions and functions of cxcl17. Our alpha fold modeling supported our initial characterization of cxcl17-gpr25 interaction. Using this as a jumping off point, we are asking whether in silico modeling in screening mode can identify the functional gpcr ligands of cxcl17 (and thus potentially of other orphan chemokines). In high throughput screening mode, we generated af2 models of cxcl17 interactions with all class a gpcrs and find that the highest scoring models include gpr25 but also two other receptors: bdkrb1, the inflammation associated bradykinin receptor, and ntsr2, the neurotensin receptor. Other receptors showed no or unfavorable interactions (defined by af2 metrics including iptm on ligand and receptor residues interacting in the ligand bind pocket of the gpcr). These in silico findings suggest the possibility of additional receptors for cxcl17 that could impact vascular and neurobiology. A major focus this year in regards to aim 2 has been on expanding and initially characterizing gpr25 deficient mice, to define the role of gpr25 in lymphocyte subset representation and distribution in mucosal tissues. We have established the colony and have evaluated basal lymphocyte subsets in the resting state. The results largely parallel those in cxcl17 deficient mice, indicating that cxcl17 is likely the only or the predominant chemokine ligand for gpr25. We have generated mixed (wt/ko) bone marrow chimeras to define the effect of gpr25 deficiency by evaluating ko lymphocyte representation in competition with wt cells in the same host.for aim 3, we continue to evaluate gpr25 expression in human and mouse disease models (scrna seq data to date from public resources). We are interested in gwas associations of gpr25 with arterial stiffness: we see significant t cell subset expression of gpr25 in data from human coronary artery disease. We are also interested in understanding the gwas associations of human blood gpr25 with autoimmune diseases especially ibd: through collaboration with dr. Montgomery, colocalization analysis indicate that gpr25 has the highest pp4 among genes in the region for ibd, crohn's disease, and ulcerative colitis, prioritizing gpr25 as the likely causal gene at this locus. We have performed rna scope on intestinal samples from ibd patients (with our collaborator and co-investigator serena tan) revealing strong cxcl17 expression within sites of pyloric metaplasia consistent with single-cell rna-seq data and supporting recruitment of gpr25 immune cells to inflamed mucosa. Recruitment of gpr25+ tregs could explain the ro

Financial Efficiency

• Mission deployment rate: 77.7%; rating input score 78
• Program expense ratio: 84.1%; rating input score 84
• Fundraising efficiency: Limited

Transparency & Controls

• Consistency checks: 100%; rating input score 100; 62nd percentile among comparable filings
• Pay-setting controls: 3 of 6 controls in place; rating input score 50
  • Compensation committee: Pass
  • Independent consultant: Missing
  • Other Form 990s reviewed: Missing
  • Written employment contract: Missing
  • Compensation survey or study: Pass
  • Board or committee approval: Pass
• Foreign activity oversight: Limited
• Grant itemization coverage: Limited
• Major donor itemization: Yes; rating input score 100
• Related-party transparency: Limited

Accountability

• Independent voting board: 23.1%; rating input score 23; 6th percentile among comparable filings
• Governance controls: 9 of 9 controls in place; rating input score 100
  • Conflict-of-interest policy: Pass
  • Whistleblower policy: Pass
  • Document-retention policy: Pass
  • CEO compensation review process: Pass
  • Other executive compensation review process: Pass
  • Form 990 shared with the board: Pass
  • Board meeting minutes documented: Pass
  • Audit committee oversight: Pass
  • Independent financial-statement audit: Pass

Sustainability

• Operating margin: 7.9%; rating input score 62; 62nd percentile among comparable filings
• Total-asset coverage ratio: 0.58; rating input score 19; 19th percentile among comparable filings
• Liabilities to assets ratio: 0.58; rating input score 23; 23rd percentile among comparable filings
• Officer compensation ratio: 7.2%; rating input score 34; 34th percentile among comparable filings

Growth

• Program expense growth: 2.3% per year; rating input score 100; 21st percentile among comparable filings
• Revenue growth: 2.4% per year; rating input score 100; 20th percentile among comparable filings
• Asset growth: 6.4% per year; rating input score 100; 45th percentile among comparable filings