Marino De Leon - US grants

9515002 De Leon When nerve cells grow they must add new cell membrane. This process requires mechanisms in the cell that carry the lipid molecules neccessary to build the membranes. In this study a specific protein that binds fatty acid has been isolated and it is now proposed to determine whether it is involved in the mechanisms that enable the nerve cell to extend processes. This work will help to understand the process of nerve growth and regeneration.

9728662 DE LEON Axons are a functional and distinct extension of the cell bodies (soma) if nerve cells. Axons transport materials that are needed to carry on the daily cell-to-cell communications that occur distant from the soma. At times of rapid axon growth, such as during normal development and axon regeneration, the nerve cell's soma (where the nucleus is located) synthesizes high levels of key proteins and phospholipids. These newly synthesized materials are efficiently transported to the end of the axon where regenerative or developmental growth occurs. Presumably, some of these newly synthesize proteins are important for axon growth. This research will determine if a recently discovered neuronal fatty acid binding protein, named DA11FABP, is required for nerve cells to grow neurites successfully. Previous studies from the PI's laboratory have shown that DA11FABP exhibits a robust induction during both developmental and regenerative axonal growth. The first goal of the study will be to create a neuronal-like cell line expressing significantly reduced levels of DA11 protein and determine if these cell lines exhibit a deficit in producing neurites during cellular differentiation. The next goal of the study is to determine what is the biological ligand of DA11 in these cell lines. This part of the study includes the production of recombinant protein and conducting binding studies to determine the affinity of the ligand(s) for DA11. The last part of the study will determine whether the biological action of DA11 during cellular differentiation is directly linked to its binding of its ligand(s). The results obtained from this study would likely increase our understanding of the molecular and cellular mechanism of axon growth and nerve regeneration.

DESCRIPTION (From Application): Maintaining public health in the 21st Century requires solving current and emerging medical problems at the local, national, and international level. The NIH has recognized that meeting this challenge demands a more ethnically diverse biomedical research community. Loma Linda University (LLU), a private health sciences institution in Southern California, is committed to student and faculty diversity. A cadre of extramurally-funded minority and non-minority faculty in the Graduate School/School of Medicine seeks support through NIGMS PAR-O0-022 to establish a comprehensive LSU-NIH Minority Student Development Program (MSDP). This program will complete the pipeline necessary to increase the number of underrepresented minority students in biomedical research programs at LLU. Specific Aim 1 is to increase the number of minority undergraduate students with a biomedical research career goal and their competitiveness for admission to Ph.D. or M.D/Ph.D. programs. Through the Undergraduate Research Scholars Program (URSP), senior college students will learn that they can play an important leadership role in solving tomorrow's medical problems. Either the Summer Research Project or the Summer/Senior Year Research Project - with their skill-building and career development modules -- will help participants compete for admission to these programs. Specific Aim 2 is to increase the number of minority graduate students who receive their Ph.D. in the biomedical sciences at LLU. Through the five-year Graduate Minority Development Program (GMDP), students will attain academic achievement and research accomplishment. A progression of skill-building modules will enhance basic communication skills, which will be translated into effective scientific communication, teaching, and career development skills. Specific Aim 3 is to increase the number of minority medical students who receive biomedical research training at LLU. Minority students in the Medical Scientist Training Program (MSTP) will participate in GMDP activities during the Ph.D. portion of their M.D./Ph.D. training. Minority medical students will participate in summer research projects through the Medical Student Research Program (MSRP). Integration of these programs within an Office of Minority Student Development (OMSD) will increase cost-effectiveness, facilitate program evaluation, and offer other benefits from synergy. Participation of all students in the monthly MSDP Seminar and Annual MSDP Research Symposium will help build a support system, encourage student-to-student mentoring, and show future Ph.D. and M.D. researchers the opportunities and benefits in collaboration.

[unreadable] DESCRIPTION (provided by applicant): Loma Linda University has a long-standing tradition for almost a century in looking at ways to create healthy and educated diverse communities. For almost three years LLU School of Medicine and Graduate School have Partnered with NIGMS in the implementation of the LLU-NIH Initiative for minority students Program to widening the pipeline of underrepresented minority students entering doctoral degrees in biomedical sciences graduate programs. The LLU-NIH IMSD application is a continuation and expansion of the original program. [unreadable] [unreadable] Specific Aim 1 is to enhance Loma Linda University Basic Science Program by increasing the number, expanding research opportunities and enhancing graduate admission qualifications of undergraduate underrepresented minority students interested in entering a Ph.D. or graduate M.D./Ph.D program. Undergraduate students will participate in biomedical research and a number of enrichment educational activities to increase their scientific proficiency and qualifications to be accepted in a Ph.D. or M.D./Ph.D. program. [unreadable] [unreadable] Specific Aim 2 is to enhance and expand Loma Linda University Basic Science Program by increasing the number of minority students enrolled and successfully graduate with a Ph.D. or MD/PhD degree in the Basic Science Program at Loma Linda University. The program includes well designed educational modules to prepare students for a career as biomedical scientists. [unreadable] [unreadable] Specific Aim 3 is to increase the number and research proficiency and health disparity awareness of minority medical students that participate in biomedical research projects at LLU. Minority medical students will participate in summer research projects, scientific seminars, symposiums to increase potential for biomedical research and health disparity awareness. The main objective of the MSRP program is to increase the number of minority medical students involved in clinical and basic science research. [unreadable] [unreadable] Integration of these programs within the Office of Minority Student Development in the Biomedical Professions (OMSDBP) increases cost-effectiveness, facilitate program implementation and evaluation, and offer other benefits from synergy. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): For a century, Loma Linda University (LLU) has played a major role in health care access and education in the Inland Empire (IE), California. For all these years LLU has supported the only medical and public health schools servicing a highly diverse community of more than three million people. The present application proposes a plan to establish the first Center for Health Disparities Research (CHDR) in the region. The five-year project proposes an innovative plan to integrate translational biomedical and community-based interdisciplinary research on health disparities with community based participatory research, partnerships for community outreach and education, and training and development of underrepresented scientists. The long-term goal of this application is to hasten the elimination of health disparities by the establishment of the LLUCHDR. The Administrative Core will provide leadership, cohesiveness and vision for the establishment of the required infrastructure to develop and strengthen LLU's capacity to focus on health disparity research. It will provide the required rules of understanding to integrate researchers from the School of Medicine, Graduate School, and the School of Public Health who share the common goal to eliminate health disparities through research, training, and outreach. The Research Core (RC) will support basic translational research with the final goal to develop interventions to modulate the "augmented state of cellular oxidative stress" (ASCOS) triggered by dietary fat, a risk factor that is seriously affecting minority populations. Studies on breast, prostate, and pancreatic cancer, diabetes, and stroke will be focused on elucidating how the development of these diseases is mediated through ASCOS-associated signaling pathways. The RC will also support research projects to understand elements of cultural competence and health care access associated with these conditions. The Research Training and Educational Core (RTEC) will integrate current health disparity training programs with the CHDR's initiative to widen the pipeline to high school & undergraduate students in health disparities research. The Community Outreach and Community Partnerships Core (COCPC) will expand existing programs with key community and government entities in the Inland Empire. The LLUCHDR will serve as a major resource for the whole region that will help researchers work with community stakeholders to reduce or eliminate health disparities in the IE and the country. [unreadable] [unreadable] [unreadable]

The P20 award by the NCMHD to LLU in 2005 was instrumental for establishing the first and only COE on health disparifies research in the Inland Empire of Southern California. The mission of this center is to reduce or eliminate health disparities in the local communifies and nafionally through a robust biomedical Research Core focused on diabetes and cancer that is interconnected with a comprehensive Research Training and Education Core, and a dynamic and successful Community Outreach and Engagement Core. The CHDMM serves a vast geographical area with a populafion of over 3.5 million. It is esfimated that by 2015, over 55% of the population in this region will belong to ethnic groups (i.e. Hispanics and African American) that traditionally have a low socioeconomic status and disadvantaged background (LSESDB). The California County Health Status Profiles 2011 ranked this region pooriy in health, and in agerelated deaths due to diabetes and cancer (2). The CHDMM is now poised for continuing expanding its sustainability and growth. The Center is currentiy comprised of 14 principal investigators with faculty appointments at the LLU Schools of Medicine and Public Health. Seven of these investigators are physically housed in contiguous laboratories within the CHDMM, focusing their research programs on biological and translational aspects of diabetes and cancer. In addition, a number of faculty members in the basic science departments ofthe School of Medicine hold adjunct member appointments in the CHDMM and contribute with their expertise in areas that complement the research mission of this center. A weekly chalk talk style informal research seminar brings together these investigators and provides a forum where original, unpublished data are discussed. CHDMM researchers interact on a regular basis to address biological aspects underiying health disparities, design translational initiatives, and create and expand programs for community education and participafion. The LLU CHDMM Annual Health Disparities Symposium also showcases research progress and brings together the biomedical research community, research trainees, university administrators, community leaders, and national leaders in health disparities. These interactions create a highly dynamic and collegial environment for collaborative research, training the next generation of health disparities researchers, and focusing community engagement.

[unreadable] DESCRIPTION (provided by applicant): For a century, Loma Linda University (LLU) has played a major role in health care access and education in the Inland Empire (IE), California. For all these years LLU has supported the only medical and public health schools servicing a highly diverse community of more than three million people. The present application proposes a plan to establish the first Center for Health Disparities Research (CHDR) in the region. The five-year project proposes an innovative plan to integrate translational biomedical and community-based interdisciplinary research on health disparities with community based participatory research, partnerships for community outreach and education, and training and development of underrepresented scientists. The long-term goal of this application is to hasten the elimination of health disparities by the establishment of the LLUCHDR. The Administrative Core will provide leadership, cohesiveness and vision for the establishment of the required infrastructure to develop and strengthen LLU's capacity to focus on health disparity research. It will provide the required rules of understanding to integrate researchers from the School of Medicine, Graduate School, and the School of Public Health who share the common goal to eliminate health disparities through research, training, and outreach. The Research Core (RC) will support basic translational research with the final goal to develop interventions to modulate the "augmented state of cellular oxidative stress" (ASCOS) triggered by dietary fat, a risk factor that is seriously affecting minority populations. Studies on breast, prostate, and pancreatic cancer, diabetes, and stroke will be focused on elucidating how the development of these diseases is mediated through ASCOS-associated signaling pathways. The RC will also support research projects to understand elements of cultural competence and health care access associated with these conditions. The Research Training and Educational Core (RTEC) will integrate current health disparity training programs with the CHDR's initiative to widen the pipeline to high school & undergraduate students in health disparities research. The Community Outreach and Community Partnerships Core (COCPC) will expand existing programs with key community and government entities in the Inland Empire. The LLUCHDR will serve as a major resource for the whole region that will help researchers work with community stakeholders to reduce or eliminate health disparities in the IE and the country. [unreadable] [unreadable] [unreadable]

Previous reports from our laboratory have found that nerve growth factor differentiated pheochromacytoma cell lines (NGFDPC12 cells) exposed to pathological levels of exogenous palmitic (PA) and stearic (SA) fatty acids -- at a level comparable to that found during hypoxia/ischemia - causes a dramatic decrease in cell viability and apoptosis. This decrease in cell survival occurs because these saturated FFA induced massive apoptosis (program cell death) during 24 hours exposure. In contrast, similar levels of arachidonic (AA) or oleic (OL), EPA or DMA FFA did not decrease the viability of these cells. The central hypothesis states that high levels of PA or SA fatty acids induce neuronal apoptosis secondary to mitochondria! dysfunction. This application will primarily focus on characterizing the apoptotic effect of PA and SA in NGFDPC12 cells and extend this analysis to primary retinal ganglion and cortical cell neurons. Specific Aim 1 will include the characterization of PA and SA-mediated caspase-independent neuronal cell death. This aim will determine the effects of these saturated FFA in the survival of rat cortical and retinal ganglion primary cells in culture. The experimental design will evaluate whether the loss of cell viability is result of apoptosis or necrosis and will determine whether the process is dependent on caspase activation. Further experiments will analyze what specific apoptotic proteins are involved in the process. Specific Aim 2 will determine whether FFAmediated neuronal cell death occurs through the mitochondrial pathway. Preliminary cDNA array analysis and Quantitative real time PCR data has identified several candidate mitochondrial genes that are involved in this process. This aim will elucidate the role of these genes by using siRNA knockdown and overexpression to modulate cellular levels. We anticipate that these studies will help us to clarify the mechanisms of how pathological levels of saturated FFA affect neuronal survival and apoptosis.

DESCRIPTION (provided by applicant): The mission of the National Institutes of Health is to improve the health status of all Americans through biomedical research and scientific training and education. To reach this goal we need to succeed in developing a diverse group of scientists ready to make breakthroughs that result in the development of novel therapies to treat current killer diseases and the reduction and ultimate elimination of current health disparities. The mission of the Initiative for Maximizing Student Diversity Program (IMSD) at Loma Linda University is to increase diversity in the cadre of students that graduate with PhD or MD-PhD degrees at this institution. To accomplish this goal, this competitive renewal application proposes a comprehensive plan that should lead to an increase in the number of underrepresented minority students (URMS) that graduate with a PhD degree from Loma Linda University. The program especially focuses in identifying and removing hurdles that can inhibit success of URMS in graduate school. The goal of the application is to double the number of URMS that graduate with a PhD degree in the biomedical sciences at LLU. The application will accomplish this goal by meeting six specific measurable objectives: (1) To recruit and support 5 new promising URMS per year that participate in the LLU- NIH IMSD program. (2) To achieve a 100% graduation rate of PhD students participating in the program. (3) To provide a supportive academic and financial environment to all LLU IMSD students. (4) To enhance the academic and research proficiency of all LLU IMSD students through participation in co-curricular activities such as modules on scientific writing and communication, research proposal development, and teaching skills. (5) To have all LLU IMSD students attend at least one major national and two regional/local scientific meetings per year, and publish a minimum of two first author manuscripts during the PhD. (6) To increase the number of graduate URMS who are proficient in the field of health disparities through participation in a 1-unit topic course on health disparities. The LLU-NIH IMSD program has been successful in reaching its goals and objectives because of the development of a robust internal pipeline of diversity programs, and a continued partnership with diversity programs from collaborating institutions around the country that share with us the vision of training a diverse workforce of biomedical scientists. Public health relevance: Finding the cure of current killer diseases in the USA requires developing a diverse cadre of biomedical scientists that are well trained and equipped to pursue cutting-edge basic and translational science research. The present application contains a comprehensive educational developmental plan that addresses well known hurdles that interfere with the aspirations of universities across the country in increasing the number of PhD graduates from students underrepresented in biomedical sciences.

The mission of the RT/EC is to eliminate health disparities in the Inland Empire and nationally through the research training and education of the next generation of health disparities researchers. To accomplish this mission we have initiated a comprehensive pipeline of health disparities research trainees at various levels in their academic development (from high school to junior faculty) that is unique and innovative in the Inland Empire in its scope and focus. A flow chart describing this pipeline (Figure 1.3) is presented above in section I- Narrative Overview of the Proposed NIMHD COE. LLU-CHDMM has the resources, the experience, and the vision to contribute to the development of future leaders in biomedical research and medicine who will be well-prepared and highly motivated to eliminate health disparities. The PI and his colleagues have an extensive track record in establishing research training and education programs targeted to students from underrepresented and health disparities populations. Renewed NIMHD funding will help us realize our vision to continue widening and strengthening the fragile pipeline of underrepresented students preparing to become biomedical researchers and doctors in service to their communities and their country. The impact of combining our individual and institutional commitment with NIH grant support will be: 1) desired measurable outcomes within the Inland Empire; 2) a model for eliminating health disparities through research training and education; 3) a comprehensive pipeline that will bring a diversity of fresh ideas to advance the biomedical sciences; and 4) expansion of health knowledge in the student's own communities, resulting in healthier lifestyle practices.

Intestinal fatty acid binding protein 2 (FABP2) exhibits a functional single nucleotide polymorphism, Ala54Thr that result in two protein variants: FABP2 Ala54 and FABP2 Thr54. The FABP2 Thr54 variant exhibits a twofold increase in fatty acid binding compared to the FABP2 Ala54 normal increase fat absorption in the intestine, and carriers may show higher risk for insulin resistance and fasting blood glucose levels. The effect of the Ala54Thr SNP has not been well characterized in Mexican Americans and recent data suggest it is associated with type 2 diabetes (T2DM) in this ethnic group. Further, about 60% of Mexican American diabetic participants in our diabetes education program are FABP2 Thr54 carriers which provide an opportunity to assess if this high incidence may contribute to the severity of the disease. This study seeks to understand the effect of the FABP2 Thr54 in Mexican Americans with T2DM. Further, we will evaluate the effect of a lifestyle intervention designed to counteract the potential negative effect ofthe FABP2 54Thr variant in participants. Individuals shown to be threonine carriers (AT/TT genotypes) may interact differently with dietary fat and may provide an unique opportunity to develop successful personalized cultural competent lifestyle interventions to reduce the impact of the disease on Mexican Americans and other affected groups. Our central hypothesis is that Mexican Americans exhibit a threonine-carrier paradox modulated by the FABP2 Ala54Thr polymorphism. The three aims of the application are: Aim 1 is to determine the effect ofthe FABP2 Ala54Thr polymorphism on fasting blood glucose and lipid levels in MA with and without T2DM. Aim 2 is to determine the effect of the FABP2 Ala54Thr polymorphism on saturated fatty acid-induced lipotoxicity. Aim 3 is to determine the dietary fat and FABP2 Ala54Thr polymorphism interactions on fasting blood glucose and lipids levels in diabetic Mexican-Americans. The completion of these aims will increase our knowledge of the effects of this SNP in T2DM health disparities in Mexican Americans and may serve as foundation for the development of future personalized prevention diabetes education program targeting this ethnic group.

Federal agencies mandate the inclusion of minority groups in study populations, yet researchers face many obstacles in reaching these underserved groups, including mistrust about the scientific community and poor past experiences. This holds true for minorities in the Southern California Inland Empire Region (IE) and San Bernardino County (SBC), where Hispanic and Black/African American communities comprise nearly 60 percent (48.1 and 9.5 percent, respectively) of the population. The IE has been identified as the most sprawling region in the U S, with a lack of transportation choices, town centers, and mixed use neighborhoods, and poorly connected street networks. There is a dearth of open spaces: one third of children 0-18 do not live within walking distance of a park, playground, or open area. Moreover, it is considered one of the unhealthiest regions of California, with only 1 of every 6 stores/restaurants selling healthy food. Race/ethnicity related health disparities are especially seen for breast cancer, prostate cancer, overweight and obesity and diabetes. For instance, breast cancer incidence in Black women compared to non-Hispanic White women is higher (124.1 cases/100,000 vs. 116.6 cases/100000, respectively), and, even more importantly. Black women suffer from higher breast cancer mortality rates than non-Hispanic Whites due to more aggressive forms of the disease. SBC has higher prostate cancer incidence in Black versus White men (135.1 cases/100,000 vs. 243 cases/100,000, respectively), and Black men have mortality rates nearly 2.5 to 6 times that of other male groups from prostate cancer. Additionally, diabetes diagnosis is higher in Latinos and Blacks vs. Whites'^^'as are complications and worse outcomes' '. Among adults, 63% are overweight or obese, and diabetes-related deaths are 120.9 per 100,000. Many areas fit the definition of high need. Medically Underserved Areas (MUAs). Despite these well documented disparities, the IE receives less per capita funding from grant-makers and foundations compared to the statewide average ($3 versus $119, respectively) and substantially less federal funding per capita ($21 vs. $1,507 nationally).

Eliminating health disparities is a major unmet need in our society. The concern is not only for equity and social justice. It will be impossible to fulfill our national goal to have a healthy population without addressing this need. Achieving this goal can be significantly enhanced by establishing health disparities research centers across the nation that are ready to implement an agenda of research, education, training and community outreach activities to support the goal of the NIMHD to eliminate disparities. Implementing these activities requires an effective administrative structure that provides support and facilitates the execution of successful initiatives and research plans. Based on our experience in the previous grant cycle, it would not be possible to operate the Center with all of its activities and maintain institutional support without a visible and efficient administrative core. The Administrative Core structure and function proposed in this application will be critical to achieve the major goals of our Center and the specific aims proposed by its other cores. For instance, we put significant attention into having an Administrative Core that addresses the needs of a young growing center. This plan provides adequate oversight through effective and experienced internal and external scientific leadership and avoids unnecessary bureaucracy and also fits well within the structure of the Center. The structure proposed for the Center was crafted in such a way that it addresses all LLU policies with respect to university centers, institutes and departments, and includes required oversight by LLU administration through an Internal Advisory panel. This was important to qualify for financial support in proportion to extramural funding generated similarly by other centers and departments. The External Advisory Panel includes a cadre of experienced national leaders in health disparities that advise the Center Director and leadership team.

DESCRIPTION (provided by applicant): Training a diverse and competent scientific workforce is indispensable to fostering innovation and producing valuable biomedical research. Achieving this goal is also critical to finding the cure for diseases affecting human kind and eliminating health disparities that have become a burden to our society at large. For over a decade Loma Linda University (LLU) has partnered with the National Institute for General Medical Sciences to address this important national challenge. The LLU-NIH Initiative for Maximizing Student Diversity Program (LLU-NIH IMSD program) has been successful in increasing institutional diversity. Further, implementation of an outcome-based educational plan has enhanced the success of students underrepresented in our biomedical/behavioral sciences doctoral programs. The IMSD program also has played a key role in the success of a robust pipeline that is nurturing socioeconomically disadvantaged and underrepresented minority (URM) students into biomedical doctoral careers. The long-term goal of the LLU-NIH IMSD program is to increase diversity at LLU by increasing the number of underrepresented students that complete a doctoral degree in the biomedical/behavioral sciences. The goal of this competitive application is to increase the average LLU URM biomedical/behavioral sciences doctoral degree graduation rate for the last five years by 50% within the next five years. This goal will be achieved by fulfilling two specific measurable objectives (SMOs). SMO 1 is to implement a co-curricular research education plan customized for IMSD trainees' needs that strategically address their career goals in the biomedical sciences. SMO 2 is to provide a continuous scholarly supportive environment for all IMSD trainees to ensure timely completion of their PhD programs and successful transition to postdoctoral training or other relevant career advancement. A cornerstone of the application's research education program plan is the implementation of Interactive Career Development Modular Workshops (IDC-MW) in scientific writing, team-based teaching, research plan development and grant writing skills, proper mentoring and coaching, effective curriculum vitae/resume development, interview mastery, time management, networking development, and principles of translational research. The IDC-MW is intended to address hurdles that hinder student's real potential to succeed as biomedical scientists. The incorporation of an Individual Development Plan (IDP) as part of the training program will strengthen the trainee's career goals and development. We anticipate that the implementation of the plan proposed in this application will foster career development of participant students and make our doctoral program more agile in training a diverse scientific workforce.