Lin Chen, Ph.D. - US grants

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Organic ferroelectric materials are important for applications of information storage, molecular motors and actuators. The advantages of organic ferroelectric materials over their inorganic counter part are their chemical tunability, processibility and self-repair capability. Therefore, understanding the structural origins in organic ferroelectric materials and their connections to the properties of the materials is crucial in developing new materials with broad applications. The proposed work will investigate the structural origins of a group of photo-switchable organic ferroelectric materials made of small aromatic organic electron donors (D) and acceptors (A) self-assembled into alternating three dimensional DADA? arrays by steady-state and time-resolved x-ray diffraction techniques at Beamline 14ID of the APS. The structural origins for such photoswitchable ferroelectric materials are structural changes either due to change of the DA distances or rotation of the side groups that form or disrupt the hydrogen bonds. Using TR-XRD, Collet, Techert, et al. carried out pioneering studies on similar type of materials with power diffraction at ESRF. We are encouraged by their success and believe that our materials can be studied by the TR-XRD with Laue diffraction on single crystals at Beanline 14ID. We would like to capture the structural origins that enable the ferroelectricity and distinguish different types of the structural changes. The proposed structural studies will be combined with single crystal ultrafast transient absorption and emission spectroscopy conducted in our labs in Northwestern University. The structural information obtained at the APS and spectroscopic and theoretical as well as chemical synthesis will enable a productive interdisciplinary research to discover, character, and applying new materials.

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, reaching epidemic proportions in the aging population and causing considerable morbidity, mortality, and socioeconomic burden. AF is primarily a disease of older people-84% are older than 65 years. Moreover, the incidence of AF sequelae such as stroke increases with advancing age. Recently, indices of arterial structure and function, such as carotid intima-media thickness (cIMT) and pulse pressure (a surrogate of arterial stiffness) have been shown to be associated with AF. There is a potential mechanism for this association: structural and functional changes in the vasculature lead to hypertension, left ventricular hypertrophy, and finally, structural remodeling in the atria. However, several knowledge gaps remain. It is unknown whether cIMT measurement improves risk prediction of AF, over and above established risk factors for AF. In addition, other indices of arterial stiffness such as carotid distensibility have not been studied in relation to AF in prospective cohort studies. Furthermore, very little is known about whether cIMT, carotid distensibility, or pulse wave velocity (PWV) predicts important clinical sequelae of AF, such as ischemic stroke and death. Identification of other indices of arterial structure and function that improve prediction of AF an its sequelae will enable us to identify individuals who will benefit from preventive interventions, thus reducing AF burden in the elderly population. In addition, if cIMT, carotid distensibility, an PWV measurements are found to improve risk prediction of AF, these findings will reinforce an emerging conceptual viewpoint on the pathophysiology of AF, specifically, that AF is not purely an electrophysiological disorder, but may be a consequence of vascular disease. In this project, we will evaluate the extent to which cIMT, carotid distensibility, and PWV are associated with AF incidence. We will also evaluate the discriminatory power of these novel risk factors, the extent to which these risk factors improve accuracy and calibration of predictive risk models, and the ability of these risk factors to improve risk classification. Our overall hypothesis is that indice of arterial structure and function improve risk prediction of AF and its sequelae. We will test our hypothesis for cIMT and carotid distensibility in an NIH- sponsored prospective biracial cohort study-Atherosclerosis Risk in Communities (ARIC) and replicate our findings in the Cardiovascular Health Study (CHS) and the Rotterdam Study (RS). We will evaluate the role of PWV in the RS. We will leverage the extensive phenotypic data, more than 3,900 incident AF cases, more than 2,500 deaths and 500 incident ischemic stroke events in participants with AF in the 3 cohorts to achieve the following specific aims: 1) Identify arterial indices that improve risk prediction of AF, 2) Identify arterial indices that improve risk prediction of ischemic strokein AF, and 3) Establish which arterial indices enhance risk prediction of all-cause and cardiovascular mortality in AF.

In this project funded by Chemical Structure, Dynamics and Mechanisms B program of Chemistry Division, Professors Lin Chen of Northwestern University and Felix Castellano of North Carolina State University are developing spectroscopic and synthetic methods to investigate how multiple metal centers in transition metal complexes (TMCs) act cooperatively to convert and accumulate energy from sunlight to multiple electronic potentials that ultimately will drive catalytic reactions for generating fuels. The proposed research is in line with the NSF Strategic and Performance Goals to transform the frontiers and innovate for society. The knowledge obtained through the proposed studies could be transformative for the chemical sciences and will greatly enhance our ability to rationally design chemical materials/devices for catalysis, optoelectronics and energy sustainability. The research activity engages university graduate students to use the advanced laser facility for characterization and advanced chemistry lab facilities for materials synthesis, providing them with a unique training ground for the development of multidisciplinary expertise. Such training is urgently needed for the next generation STEM workforce in order to explore the frontier of chemical science and to keep the US globally competitive at the frontiers of knowledge. The proposed research/education activities are integrated with public outreach and mentoring aimed at young scientists, including undergraduate students inside and outside of the University (especially female, minority, and underrepresented local college students) through collaborative training, summer school and education focused symposiums.

This work aims at controlling materials processes at the level of electrons by engineering structural factors to influence intramolecular electronic interactions and system-bath interactions on the time scale of coherent electronic and atomic motions. The mechanistic details enabling multiple-electron conversion will be investigated by newly developed two-dimensional electronic spectroscopy (2DES) and optical anisotropy spectroscopy applied to new molecular architectures. The proposed work aims at understanding intrinsic electronic couplings between the multiple metal centers TMCs and their influence on photochemical reactions. The work will engineer intrinsic coherent motions in a series of di-platinum complexes via systematically varying structural factors, such as the inter-platinum distances as well as the steric hindrance/energetics/size/conjugation of the ligands, resulting in systematic changes of the energy levels of the molecular orbitals. The researchers will use external perturbations, i.e. laser pulses, to shift electron density on a time scale faster than the period of the ground state Pt-Pt stretch, and follow with systematic investigations of dipole correlations by transient optical anisotropy, electronic couplings by two-dimensional electronic spectroscopy. They will further investigate the implications of these coherent motions in chemical and photochemical processes.

? DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is a serious public health problem because of its increasing incidence and prevalence in the aging population and its association with elevated risks of cardiovascular (CV) events and death. Our understanding of the risk factors and complications of AF is based mostly on studies that rely on its clinical recognition when a patient presents with symptoms; research on patients with cardiac implantable electronic devices indicates that a large proportion of AF episodes are not symptomatic (subclinical AF). Moreover, most studies have evaluated AF in a binary fashion-present or absent-and have not investigated AF burden (% time a person is in AF). Therefore, many knowledge gaps remain regarding AF, particularly in the elderly in whom AF exerts its greatest toll: the prevalence of subclinical AF, determinants of AF burden, and prognostic significance of AF burden all need clarification. This proposal will comprehensively define the prevalence, atherosclerosis risk factors, and clinical significance of AF and AF burden detected by a novel ambulatory ECG monitor in a biracial community-dwelling elderly cohort]. We will apply the Zio?XT Patch-an innovative non-invasive, leadless, 2-week continuous ECG recording device-to 4,000 participants (age range, 75-94 years) in the Atherosclerosis Risk in Communities (ARIC) study who will return for a planned visit 6 (V6) exam in 2016-19 and leverage the strengths of the ARIC study (extensive measurements and phenotypic data, biracial nature of the cohort, and continuous surveillance for future events) to investigate these aims: (1) [In elderly ARIC participants without a known diagnosis of AF, we will use the ECG monitor to define the prevalence of subclinical AF and AF burden, and identify subgroups with high prevalence of subclinical AF], (2) Assess the association of (a) [markers of atherosclerosis with AF and AF burden on ECG monitor in older age], (b) modifiable atherosclerosis risk factors over the previous 30 years (V1:1987-89 to V5:2011-13) with AF and AF burden on ECG monitor in older age, and (3) Quantify the relationship of AF burden in the elderly to risk of (a) [composite of nonfatal ischemic stroke, nonfatal myocardial infarction, heart failure hospitalization, and CV death], and (b) cognitive decline or dementia. [Our project may have important public health and clinical impact. First, by defining subgroups of the elderly with the highest prevalence of subclinical AF, we can target screening for subclinical AF with ambulatory ECG monitoring. Second, this project may reinforce atherosclerosis as a fundamental component in AF pathogenesis which will support a shift in strategy from one that is focused heavily on rhythm or rate management to a comprehensive one that also includes optimal control of atherosclerosis risk factors, including intensive intervention on midlife atherosclerosi risk factors to prevent AF in older age. Third, we may define AF burden as a clinically important measure, thus supporting efforts to reduce AF burden. Finally, by estimating the absolute risks of CV outcomes by different levels of AF burden, this project may elucidate the thresholds for treating AF.]

Atrial fibrillation (AF) is a serious public health problem because of its increasing prevalence in the aging population and its association with elevated risks of ischemic stroke, dementia, heart failure, and death. Recent evidence suggests that an increased stroke risk is also observed in patients with left atrial (LA) enlargement, even in the absence of AF, and that the vast majority of ischemic strokes are not temporally related to AF episodes. These observations raise the tantalizing question whether it is AF or the underlying LA substrate that causes the cardiovascular (CV) outcomes attributed to AF. This proposal will test our hypothesis: It is the abnormal LA substrate of impaired function and/or enlargement, and not AF per se, that is the principal driver of adverse outcomes currently attributed to AF, such as cerebral infarct and cognitive decline. To test this hypothesis, we will not only assess LA enlargement, but also impaired LA function, in relation to development of new MRI-defined brain infarcts and cognitive change, accounting for AF. We will leverage the extensive tests that were performed on Atherosclerosis Risk in Communities (ARIC) Study participants at visit 5 (V5, 2011-13) as baseline data: cognitive tests, 2D-echocardiograms (2DE), and brain MRI scans. We will measure LA function on 3,600 2DEs that were performed at V5 and leverage the data collected by 2 other ancillary studies at V6 and 7 (2016-19): (1) heart rhythm monitoring on 4,000 participants by Zio?XT Patch (R01HL126637), and (2) repeat brain MRI scans on 1,000 participants (R01AG05449). Cognitive tests will be repeated and mild cognitive impairment (MCI) and dementia will be adjudicated as part of the V6 and 7 exams. By measuring LA function from V5 2DEs and efficiently leveraging the data collected at V5 and from V6 and 7 ancillary studies, we will accomplish these specific aims: (1) Evaluate the prospective association of LA abnormality with new MRI cerebral infarcts, cognitive change, and incident MCI or dementia, with and without adjusting for AF; (2) Evaluate the prospective association of AF with new MRI cerebral infarcts, cognitive change, and incident MCI or dementia, with and without adjusting for LA abnormality; (3) Define mechanisms for AF-related cognitive decline by evaluating the associations of (a) LA abnormality or AF with longitudinal changes in specific brain MRI findings; (b) LA abnormality or AF with cognitive change, adjusting for clinical ischemic stroke, MRI cerebral infarcts, or other brain MRI abnormalities. If our hypothesis is confirmed, this project will have important public health and clinical impact. Our findings may (1) shift our attention to the atrial substrate as the principal driver of adverse outcomes, re-directing future efforts to discover novel strategies to prevent LA abnormality, in contrast to the current focus on rhythm control of established AF, and (2) motivate future clinical trials to test anticoagulation for patients with LA abnormality to prevent stroke. Ultimately, this project will underscore the importance of the underlying abnormal atrial substrate in understanding AF-related morbidities, and consequently advance the science and clinical practice of AF.

This K24 grant will provide the PI, Dr. Lin Yee Chen, a midcareer NIH-funded patient-oriented research (POR) investigator, with the protected time and support needed to (1) accelerate his current trajectory in mentoring junior clinicians and investigators who are conducting POR in cardiovascular (CV) science, (2) acquire additional training in mentoring methods, machine learning, and omics science, (3) promote his current research that aims to define the mechanisms underlying the relationship of the abnormal atrial substrate?atrial cardiomyopathy?and atrial fibrillation (AF) to ischemic stroke and other CV outcomes. Trainees in his AF Clinical Research Group will be recruited from the NIH-funded T32 training programs in the University of Minnesota's Division of Cardiology, Division of Epidemiology, and Division of Biostatistics; Department of Medicine Physician Scientist Training Program; KL2 and TL1 Programs of the CTSI; and graduate programs (MS in Clinical Research, MPH, and PhD) in the School of Public Health. For his career development, Dr. Chen will hone his mentoring skills and learn new skills in cutting-edge areas (machine learning and omics science) through focused study, selected coursework, seminars, and guidance from senior collaborators with domain expertise. Finally, this grant will support a research project that is based on the Atherosclerosis Risk in Communities (ARIC) Study, which extends Dr. Chen?s ongoing work to elucidate the role of atrial cardiomyopathy in driving AF-related outcomes. The specific aims are: (1) Identify atrial cardiomyopathy subtypes by using machine learning approaches to analyze the extensive data at ARIC Visit 5 (2011-13): clinical, 2D-echocardiographic, heart rate variability, arterial stiffness, ECG, and multi-omics data, (2) Evaluate association of subtypes with ischemic stroke and other CV outcomes, and (3) Discover specific risk factors for subtypes by analyzing risk factor measures collected at Visits 1-4 (1987-98). Crucially, findings will be validated in 2 independent community-based cohorts: Cardiovascular Health Study (CHS) and Multi-Ethnic Study of Atherosclerosis (MESA). This project has significant impact: (1) This K24 grant will provide the PI with the protected time to enhance his current mentoring of trainees involved in POR. By assembling a team of senior collaborators that comprise experts in mentoring, data science, and molecular epidemiology, the PI provides an outstanding platform for his mentees to acquire cutting-edge skills in POR, (2) By resolving heterogeneity in atrial cardiomyopathy, the team will advance the NIH?s Precision Medicine initiative by personalizing current treatment for patients based on biological underpinnings, (3) The findings will lead to a clinically meaningful improvement in classification of stroke risk in patients with AF, which will improve patient outcomes, (4) By efficiently leveraging existing resources of deeply phenotyped NHLBI cohorts, this project will fill critical knowledge gaps in prevention and treatment, thus achieving a sustained and powerful impact on CV public health, clinical practice, and education of the next generation of researchers in POR.