Soluble Glycoprotein VI Predicts Abdominal Aortic Aneurysm Growth Rate and is a Novel Therapeutic Target.

A common feature in patients with abdominal aortic aneurysms (AAA) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation impacts the pathogenesis of AAA. Using RNA-sequencing, we identify that the platelet-associated transcripts are significantly enriched in the ILT compared to the adjacent aneurysm wall and healthy control aortas. We found that the platelet specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of AAA patients. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in two independent AAA patient cohorts is highly predictive of a AAA diagnosis and associates more strongly with aneurysm growth rate when compared to D-dimer in humans. Finally, intervention with the anti-GPVI antibody (JAQ1) in mice with established aneurysms blunted the progression of AAA in two independent mouse models. In conclusion, we show that levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, where none currently exist.

Gut Microbiota-Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and Apoptotic Mechanisms.

BACKGROUND: Large-scale human and mechanistic mouse studies indicate a strong relationship between the microbiome-dependent metabolite trimethylamine N-oxide (TMAO) and several cardiometabolic diseases. This study aims to investigate the role of TMAO in the pathogenesis of abdominal aortic aneurysm (AAA) and target its parent microbes as a potential pharmacological intervention. METHODS: TMAO and choline metabolites were examined in plasma samples, with associated clinical data, from 2 independent patient cohorts (N=2129 total). Mice were fed a high-choline diet and underwent 2 murine AAA models, angiotensin II infusion in low-density lipoprotein receptor-deficient (Ldlr-/-) mice or topical porcine pancreatic elastase in C57BL/6J mice. Gut microbial production of TMAO was inhibited through broad-spectrum antibiotics, targeted inhibition of the gut microbial choline TMA lyase (CutC/D) with fluoromethylcholine, or the use of mice genetically deficient in flavin monooxygenase 3 (Fmo3-/-). Finally, RNA sequencing of in vitro human vascular smooth muscle cells and in vivo mouse aortas was used to investigate how TMAO affects AAA. RESULTS: Elevated TMAO was associated with increased AAA incidence and growth in both patient cohorts studied. Dietary choline supplementation augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad-spectrum antibiotics. Treatment with fluoromethylcholine ablated TMAO production, attenuated choline-augmented aneurysm initiation, and halted progression of an established aneurysm model. In addition, Fmo3-/- mice had reduced plasma TMAO and aortic diameters and were protected from AAA rupture compared with wild-type mice. RNA sequencing and functional analyses revealed choline supplementation in mice or TMAO treatment of human vascular smooth muscle cells-augmented gene pathways associated with the endoplasmic reticulum stress response, specifically the endoplasmic reticulum stress kinase PERK. CONCLUSIONS: These results define a role for gut microbiota-generated TMAO in AAA formation through upregulation of endoplasmic reticulum stress-related pathways in the aortic wall. In addition, inhibition of microbiome-derived TMAO may serve as a novel therapeutic approach for AAA treatment where none currently exist.

Venous thromboembolic outcomes in patients with lymphedema and lipedema: An analysis from the National Inpatient Sample.

BACKGROUND: Patients with lymphedema and lipedema share physical exam findings that may lead to misdiagnosis. Poor mobility is common in patients with obesity and patients with lymphedema and lipedema. This may constitute a risk factor for venous thromboembolism (VTE). Our objective was to evaluate the association of VTE in obese patients with lymphedema and lipedema. METHODS: The National Inpatient Sample (NIS) was searched from 2016 to 2020 to identify hospital admissions of obese female patients with lymphedema and lipedema. Patients were analyzed in the context of presence or absence of VTE while adjusting for complex cluster sampling techniques. Predictors of VTE were accessed by multivariable regression. RESULTS: Lymphedema was identified in 189,985 patients and lipedema in 50,645 patients. VTE was observed in 3.12% (n = 374,210) of patients with obesity. In patients with obesity, VTE was more common in patients with lymphedema than without (2.6% vs 1.6%; p < 0.01). Similarly, VTE was more common in patients with lipedema than without (0.6% vs 0.4%; p < 0.01). After multivariable logistic regression, VTE events in obese patients with lymphedema were higher versus without (OR 1.6; CI 1.08-2.43; p = 0.02). Similarly, VTE events were more common in obese patients with lipedema versus obese patients without lipedema (OR 1.20; CI 1.03-1.41; p = 0.02). CONCLUSIONS: In this hypothesis-generating study, lymphedema and lipedema show a positive association with VTE after adjusting for baseline patient characteristics such as obesity, which is a known independent risk factor for VTE. Mechanisms whereby lymphedema and lipedema are associated with VTE should be investigated.

SARS-CoV-2 Initiates Programmed Cell Death in Platelets.

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Sex-Specific Platelet Activation Through Protease-Activated Receptors Reverses in Myocardial Infarction.

OBJECTIVE: The platelet phenotype in certain patients and clinical contexts may differ from healthy conditions. We evaluated platelet activation through specific receptors in healthy men and women, comparing this to patients presenting with ST-segment-elevation myocardial infarction and non-ST-segment-elevation myocardial infarction. Approach and Results: We identified independent predictors of platelet activation through certain receptors and a murine MI model further explored these findings. Platelets from healthy women and female mice are more reactive through PARs (protease-activated receptors) compared with platelets from men and male mice. Multivariate regression analyses revealed male sex and non-ST-segment-elevation myocardial infarction as independent predictors of enhanced PAR1 activation in human platelets. Platelet PAR1 signaling decreased in women and increased in men during MI which was the opposite of what was observed during healthy conditions. Similarly, in mice, thrombin-mediated platelet activation was greater in healthy females compared with males, and lesser in females compared with males at the time of MI. CONCLUSIONS: Sex-specific signaling in platelets seems to be a cross-species phenomenon. The divergent platelet phenotype in males and females at the time of MI suggests a sex-specific antiplatelet drug regimen should be prospectively evaluated.

Effect of aspirin on short-term outcomes in hospitalized patients with COVID-19.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is an ongoing viral pandemic marked by increased risk of thrombotic events. However, the role of platelets in the elevated observed thrombotic risk in COVID-19 and utility of antiplatelet agents in attenuating thrombosis is unknown. We aimed to determine if the antiplatelet effect of aspirin may mitigate risk of myocardial infarction, cerebrovascular accident, and venous thromboembolism in COVID-19. We evaluated 22,072 symptomatic patients tested for COVID-19. Propensity-matched analyses were performed to determine if treatment with aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) affected thrombotic outcomes in COVID-19. Neither aspirin nor NSAIDs affected mortality in COVID-19. Thus, aspirin does not appear to prevent thrombosis and death in COVID-19. The mechanisms of thrombosis in COVID-19, therefore, appear distinct and the role of platelets as direct mediators of SARS-CoV-2-mediated thrombosis warrants further investigation.

Diagnostic approach and management of genetic aortopathies.

Aortic aneurysms were the primary cause of nearly 10,000 deaths in 2014 according to data from the Centers for Disease Control and may involve segments of the thoracic or abdominal aorta. Thoracic aortic aneurysms and dissections are more commonly associated with an underlying genetic etiology. In the past several decades, in parallel with the burst of new genome sequencing technologies, a number of genetic aortopathies have been identified. These have provided important insights into the molecular mechanisms of aneurysmal disease, but pose challenges in clinical practice as there are limited consensus recommendations at this time. In this review, we aim to address the pathophysiology, clinical presentation, and treatment considerations in the key heritable thoracic aortopathies.

SARS-CoV-2 and pulmonary embolism: who stole the platelets?

BACKGROUND: Patients infected with SARS-CoV-2 often develop venous and arterial thrombosis. The high patient mortality is partly attributed to thrombotic events. An emerging trend is the presence of immunological phenomena including antiphospholipid antibodies which may promote thrombosis. The mechanism for these observations is not clear though many patients with SARS-CoV-2 develop thrombocytopenia. CASE PRESENTATION: We describe a patient with SARS-CoV-2 pneumonitis who presented with intermediate risk pulmonary embolism (PE). Careful attention to his daily platelet count suggested the possibility of immune mediated heparin-induced thrombocytopenia (HIT) which was confirmed by laboratory testing and resolved when anticoagulation was switched to a direct thrombin inhibitor. CONCLUSIONS: Since excessive platelet activation and in situ thrombosis occur in HIT, this case underscores the need to consider that thrombocytopenia in patients with SARS-CoV-2-most of whom receive heparinoids-may be unrecognized HIT. A central role for the platelet in the etiology of thrombosis during the COVID-19 pandemic should be explored.

Jugular Venous Aneurysm.

Jugular venous aneurysms are uncommon and can involve the internal, external, and anterior jugular veins. These aneurysms may be congenital or acquired secondary to malignancy, inflammation, trauma or arteriovenous fistulas. Treatment strategies are not clearly defined and involve either surveillance of asymptomatic aneurysms or resection, excision, and ligation of the aneurysmal vein. In this case series, we discuss the presentation, diagnostics, treatments and outcomes in 3 patients with jugular venous aneurysms.

Perceptions of resuscitation care among in-hospital cardiac arrest responders: a qualitative analysis.

BACKGROUND: In-hospital cardiac arrests (IHCA) occur commonly and are associated with poor survival and variable outcomes. This study aimed to directly survey IHCA responders to understand their perceptions of resuscitation care. METHODS: As part of a quality improvement initiative, we surveyed participating providers of IHCAs at our institution from Jan 2014 to May 2016. The survey included unstructured free text feedback, which was the focus of this study. We systematically coded the free text and organized identifiable latent themes using thematic analysis. We used the natural timeline of an IHCA - pre-arrest, arrest, and post-arrest - for organization of the identifiable latent themes, and created a separate category for holistic remarks that arched across the timeline. RESULTS: We identified 172 IHCAs with a mean of 1.7 responses per arrest (range: 1-8 responses). The mean age of this patient population was 59 years at the time of arrest, and 107 (62%) were men. We identified several themes - [1] issues around code activation and code status characterized the pre-arrest period [2] ,team interactions and issues around supplies/equipment dominated the intra-arrest period, and [3] code cessation and transitions of care typified the post-arrest period. Holistic remarks focused on attentiveness paid by the arrest team to patient comfort and family. Some comments reflected positive experiences but most focused on areas of improvement consistent with the initiative's purpose. In certain cases, we identified a tension between the need to balance established resuscitation protocols with flexibility required by real-life circumstances. CONCLUSIONS: Directly surveying those who participated in IHCAs led to novel insights about their experiences. Our findings suggest that parsing through such qualitative feedback can help hospitals identify areas of improvement, modulate expectations, temper emotions, and refine protocols.

Aortic Valve Replacement in Patients with End-Stage Liver Disease: A Modified Perfusion Concept in High-Risk Patients.

BACKGROUND AND AIM OF THE STUDY: Cardiac surgery with the use of cardiopulmonary bypass in patients with end-stage liver disease is associated with a high risk of postoperative morbidity and mortality due to bleeding, and a high incidence of bacterial infection with associated secondary complications. Minimized extracorporeal perfusion circuits (MECCs) with a lower priming volume, reduced foreign surface area, and interdisciplinary preoperative and postoperative treatment may address these negative effects and improve patient outcomes. The study aim was to evaluate the feasibility of the MECC and optimized supportive therapy in patients with advanced-stage liver cirrhosis. METHODS: Seven consecutive male patients (median age 56 years; range 54-67 years) with hepatic cirrhosis (Child-Pugh score B, median Model of End-stage Liver Disease (MELD) score 14; range 8-26) underwent aortic valve replacement (AVR) using MECC. Supportive preoperative and postoperative management included digestive decontamination, antioxidant supplements, and adjusted anti-infective therapy. RESULTS: All patients survived the hospital course, with 30-, 60-, and 90-day mortality of 0%. The median intensive care unit and in-hospital lengths of stay were 3 days (range: 1-5 days) and 13 days (range: 5-18 days), respectively. One patient required reexploration due to bleeding, and another suffered from a seizure without permanent neurologic deficits. No patient required new-onset hemodialysis. At a median follow up of 22 months (range: 2-46 months) all patients were alive but displayed only minor improvements in cardiac symptoms (median NYHA class III (range: II-III) at baseline versus II (range: II-III) postoperatively) and hepatic symptoms. CONCLUSION: Conventional AVR in patients with advanced-stage liver cirrhosis using MECC and optimal medical treatment is feasible. Further studies are required to evaluate the impact of alternative interventional techniques in this high-risk cohort.

Antiplatelet Therapy, Abdominal Aortic Aneurysm Progression, and Clinical Outcomes.

Importance: Preclinical studies suggest a potential role for aspirin in slowing abdominal aortic aneurysm (AAA) progression and preventing rupture. Evidence on the clinical benefit of aspirin in AAA from human studies is lacking. Objective: To investigate the association of aspirin use with aneurysm progression and long-term clinical outcomes in patients with AAA. Design, Setting, and Participants: This was a retrospective, single-center cohort study. Adult patients with at least 2 available vascular ultrasounds at the Cleveland Clinic were included, and patients with history of aneurysm repair, dissection, or rupture were excluded. All patients were followed up for 10 years. Data were analyzed from May 2022 to July 2023. Main Outcomes and Measures: Clinical outcomes were time-to-first occurrence of all-cause mortality, major bleeding, or composite of dissection, rupture, and repair. Multivariable-adjusted Cox proportional-hazard regression was used to estimate hazard ratios (HR) for all-cause mortality, and subhazard ratios competing-risk regression using Fine and Gray proportional subhazards regression was used for major bleeding and composite outcome. Aneurysm progression was assessed by comparing the mean annualized change of aneurysm diameter using multivariable-adjusted linear regression and comparing the odds of having rapid progression (annual diameter change >0.5 cm per year) using logistic regression. Results: A total of 3435 patients (mean [SD] age 73.7 [9.0] years; 2672 male patients [77.5%]; 120 Asian, Hispanic, American Indian, or Pacific Islander patients [3.4%]; 255 Black patients [7.4%]; 3060 White patients [89.0%]; and median [IQR] follow-up, 4.9 [2.5-7.5] years) were included in the final analyses, of which 2150 (63%) were verified to be taking aspirin by prescription. Patients taking aspirin had a slower mean (SD) annualized change in aneurysm diameter (2.8 [3.0] vs 3.8 [4.2] mm per year; P = .001) and lower odds of having rapid aneurysm progression compared with patients not taking aspirin (adjusted odds ratio, 0.64; 95% CI, 0.49-0.89; P = .002). Aspirin use was not associated with risk of all-cause mortality (adjusted HR [aHR], 0.92; 95% CI, 0.79-1.07; P = .32), nor was aspirin use associated with major bleeding (aHR, 0.88; 95% CI, 0.76-1.03; P = .12), or composite outcome (aHR, 1.16; 95% CI, 0.93-1.45; P = .09) at 10 years. Conclusions: In this retrospective study of a clinical cohort of 3435 patients with objectively measured changes in aortic aneurysm growth, aspirin use was significantly associated with slower progression of AAA with a favorable safety profile.

Glycoprotein VI is Critical for the Detection and Progression of Abdominal Aortic Aneurysms.

A common feature in patients with abdominal aortic aneurysms (AAA) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation impacts the pathogenesis of AAA. Using RNA-sequencing, we identify that the platelet-associated transcripts are significantly enriched in the ILT compared to the adjacent aneurysm wall and healthy control aortas. We found that the platelet specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of AAA patients. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in two independent AAA patient cohorts is highly predictive of a AAA diagnosis and associates more strongly with aneurysm growth rate when compared to D-dimer in humans. Finally, intervention with the anti-GPVI antibody (J) in mice with established aneurysms blunted the progression of AAA in two independent mouse models. In conclusion, we show that levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, where none currently exist. KEY POINTS: Soluble glycoprotein VI, which is a platelet-derived blood biomarker, predicts a diagnosis of AAA, with high sensitivity and specificity in distinguishing patients with fast from slow-growing AAA.Blockade of glycoprotein VI in mice with established aneurysms reduces AAA progression and mortality, indicating therapeutic potential.

Racial Differences and In-Hospital Outcomes Among Hospitalized Patients with COVID-19.

OBJECTIVE: There is a paucity of data on how race affects the clinical presentation and short-term outcome among hospitalized patients with SARS-CoV-2, the 2019 coronavirus (COVID-19). METHODS: Hospitalized patients ≥ 18 years, testing positive for COVID-19 from March 13, 2020 to May 13, 2020 in a United States (U.S.) integrated healthcare system with multiple facilities in two states were evaluated. We documented racial differences in clinical presentation, disposition, and in-hospital outcomes for hospitalized patients with COIVD-19. Multivariable regression analysis was utilized to evaluate independent predictors of outcomes by race. RESULTS: During the study period, 3678 patients tested positive for COVID-19, among which 866 were hospitalized (55.4% self-identified as Caucasian, 29.5% as Black, 3.3% as Hispanics, and 4.7% as other racial groups). Hospitalization rates were highest for Black patients (36.6%), followed by other (28.3%), Caucasian patients (24.4%), then Hispanic patients (10.7%) (p < 0.001). Caucasian patients were older, and with more comorbidities. Absolute lymphocyte count was lowest among Caucasian patients. Multivariable regression analysis revealed that compared to Caucasians, there was no significant difference in in-hospital mortality among Black patients (adjusted odds ratio [OR] 0.53; 95% confidence interval [CI] 0.26-1.09; p = 0.08) or other races (adjusted OR 1.62; 95% CI 0.80-3.27; p = 0.18). Black and Hispanic patients were admitted less frequently to the intensive care unit (ICU), and Black patients were less likely to require pressor support or hemodialysis (HD) compared with Caucasians. CONCLUSIONS: This observational analysis of a large integrated healthcare system early in the pandemic revealed that patients with COVID-19 did exhibit some racial variations in clinical presentation, laboratory data, and requirements for advanced monitoring and cardiopulmonary support, but these nuances did not dramatically alter in-hospital outcomes.

Platelet olfactory receptor activation limits platelet reactivity and growth of aortic aneurysms.

As blood transitions from steady laminar flow (S-flow) in healthy arteries to disturbed flow (D-flow) in aneurysmal arteries, platelets are subjected to external forces. Biomechanical platelet activation is incompletely understood and is a potential mechanism behind antiplatelet medication resistance. Although it has been demonstrated that antiplatelet drugs suppress the growth of abdominal aortic aneurysms (AAA) in patients, we found that a certain degree of platelet reactivity persisted in spite of aspirin therapy, urging us to consider additional antiplatelet therapeutic targets. Transcriptomic profiling of platelets from patients with AAA revealed upregulation of a signal transduction pathway common to olfactory receptors, and this was explored as a mediator of AAA progression. Healthy platelets subjected to D-flow ex vivo, platelets from patients with AAA, and platelets in murine models of AAA demonstrated increased membrane olfactory receptor 2L13 (OR2L13) expression. A drug screen identified a molecule activating platelet OR2L13, which limited both biochemical and biomechanical platelet activation as well as AAA growth. This observation was further supported by selective deletion of the OR2L13 ortholog in a murine model of AAA that accelerated aortic aneurysm growth and rupture. These studies revealed that olfactory receptors regulate platelet activation in AAA and aneurysmal progression through platelet-derived mediators of aortic remodeling.

SARS-CoV-2 Receptors are Expressed on Human Platelets and the Effect of Aspirin on Clinical Outcomes in COVID-19 Patients.

Coronavirus disease-2019 (COVID-19) caused by SARS-CoV-2 is an ongoing viral pandemic marked by increased risk of thrombotic events. However, the role of platelets in the elevated observed thrombotic risk in COVID-19 and utility of anti-platelet agents in attenuating thrombosis is unknown. We aimed to determine if human platelets express the known SARS-CoV-2 receptor-protease axis on their cell surface and assess whether the anti-platelet effect of aspirin may mitigate risk of myocardial infarction (MI), cerebrovascular accident (CVA), and venous thromboembolism (VTE) in COVID-19. Expression of ACE2 and TMPRSS2 on human platelets were detected by immunoblotting and confirmed by confocal microscopy. We evaluated 22,072 symptomatic patients tested for COVID-19. Propensity-matched analyses were performed to determine if treatment with aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) affected thrombotic outcomes in COVID-19. Neither aspirin nor NSAIDs affected mortality in COVID-19. However, both aspirin and NSAID therapies were associated with increased risk of the combined thrombotic endpoint of (MI), (CVA), and (VTE). Thus, while platelets clearly express ACE2-TMPRSS2 receptor-protease axis for SARS-CoV-2 infection, aspirin does not prevent thrombosis and death in COVID-19. The mechanisms of thrombosis in COVID-19, therefore, appears distinct and the role of platelets as direct mediators of SARS-CoV-2-mediated thrombosis warrants further investigation.

The Aortic Root: Natural History After Root-Sparing Ascending Replacement in Nonsyndromic Aneurysmal Patients.

BACKGROUND: Leaving native aortic tissue in situ in root-sparing ascending aortic replacement raises concern regarding potential later need for root reoperation or for the potential occurrence of localized dissections or rupture in the residual root. The purpose of this study was to evaluate the natural growth of the aortic root after root-sparing aortic replacement. METHODS: In all, 102 consecutive patients (mean age 61.8 ± 12.5 years; 60% male) who had undergone root-sparing aortic replacement had sufficient retrievable information regarding their aortic root diameter at postoperative baseline and follow-up imaging by computed tomography or echocardiography. The annual growth rate was evaluated and also compared according to the influence of valve morphology and concomitant aortic valve replacement. Furthermore, the years of natural history that would require for root enlargement to meet a 50 mm threshold of the root diameter were calculated. RESULTS: The estimated growth rate of the aortic root after root-sparing aortic replacement is between 0.27 and 0.51 mm per year (mean 0.41 mm, varying according to the underlying diameter) and therefore fivefold less than other aortic regions. Accordingly, a root aneurysm indicating reoperation would not be expected for 29.1 years on average. Only patients with a diameter of 45 mm or more are at risk for reoperation, and not until at least after 10.4 years have passed. Neither the valve morphology (p = 0.62) nor concomitant aortic valve replacement (p = 0.86) influenced rate of root dilation. CONCLUSIONS: In nonsyndromic patients, the aortic root is the slowest growing portion of the thoracic aorta. Leaving the native root, as in root-sparing ascending aortic replacement, is a safe approach regarding secondary root intervention for aortic root diameters of 45 mm or less.

A genetic screen identifies putative targets and binding partners of CREB-binding protein in the developing Drosophila eye.

Drosophila CREB-binding protein (dCBP) is a very large multidomain protein, which belongs to the CBP/p300 family of proteins that were first identified by their ability to bind the CREB transcription factor and the adenoviral protein E1. Since then CBP has been shown to bind to >100 additional proteins and functions in a multitude of different developmental contexts. Among other activities, CBP is known to influence development by remodeling chromatin, by serving as a transcriptional coactivator, and by interacting with terminal members of several signaling transduction cascades. Reductions in CBP activity are the underlying cause of Rubinstein-Taybi syndrome, which is, in part, characterized by several eye defects, including strabismus, cataracts, juvenile glaucoma, and coloboma of the eyelid, iris, and lens. Development of the Drosophila melanogaster compound eye is also inhibited in flies that are mutant for CBP. However, the vast array of putative protein interactions and the wide-ranging roles played by CBP within a single tissue such as the retina can often complicate the analysis of CBP loss-of-function mutants. Through a series of genetic screens we have identified several genes that could either serve as downstream transcriptional targets or encode for potential CBP-binding partners and whose association with eye development has hitherto been unknown. The identification of these new components may provide new insight into the roles that CBP plays in retinal development. Of particular interest is the identification that the CREB transcription factor appears to function with CBP at multiple stages of retinal development.