2005 — 2007 |
Halme, Adrian J |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Investigation of a Development Checkpoint in Flies @ University of California Berkeley
DESCRIPTION (provided by applicant): In order for a multicellular organism to develop properly, it must successfully coordinate the growth and differentiation of tissues across the entire organism. In cancer, the regulatory interactions between cell division and organismal development break down. In some instances, proliferating cancer cells can commandeer endogenous endocrine signals to promote tumor growth and malignancy. The experiments in this proposal investigate the perturbation of endocrine signaling by both regenerative and tumorous cell division at the initiation of metamorphosis in holometabolous insects. In the fruit fly, Drosophila melanogaster, entry into metamorphosis is promoted by the ecdysteroid hormone 20-hydroxyecdysone. However, this endocrine activation of metamorphosis is delayed if larval tissues continue to undergo additional rounds of cell division. By utilizing: a) the ability to regulate hormone levels in Drosophila by feeding exogenous hormone to larvae and adult flies, b) cell and tissue culture and c) genetic screens, I plan to identify the important genes and molecules that mediate the interaction between dividing cells and the Drosophila endocrine system.
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1 |
2012 — 2016 |
Halme, Adrian J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dissection of a Developmental Checkpoint That Preserves Regenerative Capacity
DESCRIPTION (provided by applicant): The experiments described in this proposal examine a newly defined regulatory mechanism, a developmental checkpoint - the developmental analogue of a cell-cycle checkpoint - that is activated by tissue damage during larval growth of the fruit fly, Drosophila melanogaster. This developmental checkpoint regulates systemic endocrine and metabolic signals to delay development and preserve the regenerative capacity of damaged tissues. The systemic influences on the regenerative capacity of tissues are poorly understood. Therefore, a mechanistic understanding of this developmental checkpoint will provide an important, new insight into the regulation of the systemic signals that control regenerative growth. The aims of the research described in this proposal are to build on our initial observations and further define each of the key steps within this developmental checkpoint. First, this proposal explores how retinoid signaling, which participates in checkpoint activation, functions to regulate neuroendocrine activity in the larval brain and produce developmental delay. The relevant functional localization of retinoid biosynthesis during damage will be examined using transgenic constructs, in situ hybridization, and tissue-targeted inhibition and rescue of retinoid biosynthesis. Molecular and genetic experiments will be used to determine the role of retinoids in inhibiting a neuroendocrine positive feedback loop that regulates developmental progression. Second, experiments in this proposal are designed to identify the damage signal that regulates the systemic responses to localized tissue damage. Genetic epistasis experiments will be used to test the role of Eiger, the Drosophila TNF homologue, in producing the systemic damage signal that mediates the developmental checkpoint activation. At the same time, unbiased genetic approaches will also be used to establish the identity of the damage signal. Third, this proposal examines the systemic metabolic effects produced by localized tissue damage. The effect of local tissue damage on systemic insulin signaling will be examined using several tissue-specific and systemic reporters, and the role of altered insulin signaling in checkpoint delay will be examined using tissue-targeted inhibition of the forkhead-transcription factor, dFoxo. Completion of the experiments described in this proposal will provide valuable new insights into the regulation of the systemic signals that control tissue regeneration. In addition, these experiments will reveal the mechanisms by which persistent tissue damage and inflammation can produce systemic effects on growth and endocrine control of development, which are each observed in clinical examples of persistent inflammation such as obesity-related insulin resistance and cancer cachexia. PUBLIC HEALTH RELEVANCE: The capacity of tissues to regenerate is widely varied across evolution. However, little is understood about the systemic developmental signals that govern regenerative capacity. This proposal examines a molecular mechanism by which damaged tissues regulate systemic metabolic and endocrine signals to preserve regenerative competence. Describing this mechanism will provide a greater understanding of the systemic signals that govern regenerative growth and should also provide new insights into the systemic responses to chronic tissue damage and inflammation (e.g. impaired growth, developmental delay, and cachexia) that have a profound impact on patients in a clinical setting.
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0.961 |
2020 |
Halme, Adrian J |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Identifying Developmental Pathways That Regulate Bilateral Growth Symmetry
Abstract Growth is a fundamental property of animal development. While research has uncovered many of the molecular pathways responsible for regulating tissue size, how the activity of those pathways is coordinated across different organs or tissues to produce the proportion and symmetry we observe in mature tissues remains a mystery. In this proposal, we generate an experimental model that will serve as a basis for exploring symmetric growth coordination (SGC) between paired tissues in the fruit fly Drosophila melanogaster, a genetically tractable developmental model. In Drosophila, adult appendages derive from larval tissues called imaginal discs. During larval development, damaged imaginal discs can regenerate. In previous work, my research group described how release of the relaxin hormone Dilp8 by regenerating tissues, and the activation of the Dilp8 receptor Lgr3 in the brain and endocrine tissues, coordinates the growth of regenerating and undamaged tissues to maintain appropriate adult proportion. Loss of Dilp8/Lgr3 signaling also produces an increased frequency of spontaneous growth asymmetries in the wings of mutant animals. However, the low penetrance of this phenotype makes it difficult to examine how SGC is regulated during development. To overcome this experimental difficulty, in this proposal we describe a new genetic model to look at SGC between paired tissues, such as Drosophila wings. Since male and female wings have different growth rates, bilateral sexual mosaics, or gynandromorphs, allow us to determine whether compensatory growth pathways are activated in response to growth asymmetries. Using this genetic model, our preliminary data reveals that there is growth coordination between male and female tissues in gynandromorphs. We also observe that gynandromorph development is delayed and that both male and female tissues are smaller. Both of these phenotypes are consistent with the activation of the Dilp8/Lgr3 pathway in gynandromorphs. Therefore, we propose genetic approaches to test the role of Dilp8/Lgr3 pathway in mediating SGC in gynandromorphs. Additionally, by developing a fluorescent reporter for identifying larval gynandromorphs, we will determine the developmental stages where SGC occurs and identify gene expression patterns associated with slower and faster growing tissues during growth compensation. Developmental growth compensation during early human development is associated with higher risk of long-term heath complications, including metabolic and cardiovascular disease. By examining SGC in our model, we hope to gain insights into the etiology of these compensation-induced disease states to direct clinical research towards new therapies.
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0.961 |
2021 |
Halme, Adrian J Owens, Gary K [⬀] |
R25Activity Code Description: For support to develop and/or implement a program as it relates to a category in one or more of the areas of education, information, training, technical assistance, coordination, or evaluation. |
Short-Term Training to Increase Diversity in Health-Related Research
ABSTRACT The overarching goal of the Summer Research Internship Program (SRIP) is to exploit the rich research community at the University of Virginia (UVA) to expose underrepresented undergraduate and medical students to the excitement, capabilities, rigors, and breadth of opportunities for careers in biomedical research. From its inception, the major goals of this NHLBI-supported program have been (1) to expose undergraduate students to the state-of-the-art in cardiovascular, pulmonary and hematological research; (2) to familiarize the students with the opportunities that exist for careers in research; (3) to encourage and facilitate them pursuing a career in research; and (4) to kindle and nurture a passion for doing research that truly makes a difference and leaves a mark on mankind. This application seeks support to continue this successful program, through which ten (10) undergraduate and/or post-baccalaureate students and five (5) rising second-year medical students participate in the SRIP each year. The ten-week program has three educational components. The first and most important is an immersive, hand-on research experience mentored by of one of our 56 program faculty and focused in the mission areas of the NHLBI. Second, the trainees participate in a weekly 1-hour workshop focused on developing and refining scientific communication skills appropriate for various contexts and audiences. Finally, the trainees attend a professional development luncheon series that provides instruction in successful admission to graduate and medical school, panel discussions of career options led by current students, and opportunities to interact with and learn from basic scientists, translational researchers and physician scientists. These presentations are intertwined with practical experiences focused on positioning both the undergraduate and medical student trainees for success at the next stages of their career. To date, more than 50% of the undergraduate SRIP alumni have successfully made the transition in graduate and/or medical school. Through strong mentorship, hands-on research, innovative educational initiatives, and exposure to a wide range of research and clinical care experiences, trainees in the SRIP are uniquely prepared to pursue advanced training with the ultimate goal of becoming members of a diverse biomedical workforce. !
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0.961 |