New Faculty II
$1 775 000
The applicant proposes to undertake a program of research that aims to reveal how Alzheimerís disease (AD) brain affects the biology of neural progenitor/stem cells. This aim is to understand if generation of new neurons (neurogenesis) in AD is dysfunctional and leads to a vulnerable environment for later occurring neurodegeneration. It will also investigate systemically what mechanisms are altered in the AD neural progenitors/stem cells that will generate potential drug targets. Using a broad molecular pproach to the study of NPC biology in AD-like environment, the candidate plans to answer two crucial and interrelated questions: first, how and why neurogenesis is altered in the AD brain and second, does adult neurogenesis contributes to the development of AD and related dementias. The study is built on the candidateís expertise in neural stem cell biology, functional neurogenomics and animal experimentation. This is a highly integrative approach that takes advantage of vast resources near the applican’s institution. Two experts in the neural stem cell biology are involved as mentors and co-investigators. Therefore, the chances for success are high. The project approaches a new and highly attractive area of investigation and the results will have direct impact on the design of future neuroreplacement therapies for AD and other neurological diseases.
Statement of Benefit to California:
It is estimated that the costs for Alzheimer’s disease (AD) patients in California will increase 83.5 percent in the period 2000 ($26 billion) to 2020 ($47.5 billion) and will grow another 60% from 2020 to 2040 ($75.5 billion). Total costs of caring for AD patients will nearly triple between 2000 and 2040 (Fox et al, 2001). The rapid aging of the U.S. population and Californians in particular makes it necessary to aggressively invest in the development of novel therapies reducing societal burden of Alzheimer's disease in the nearest future. A major challenge not addressed by existing therapeutic interventions for AD is the regeneration of lost neurons and neural circuitry to restore cognitive function. In the light of the above, stem cell based cell replacement therapies look particularly attractive and indeed this approach could revolutionize the whole field. However, mounting evidence indicates neurogenesis might be altered in AD brain raising the question of how feasible such approach would be if the AD environment proves to be toxic for newly introduced neural progenitor cells. This proposal aims to establish and understand the relationship between AD and functional neurogenesis allowing us to predict the possible outcomes of the stem cell therapy and manipulate the AD brain environment for more efficient cell replacement strategies. This work will also establish the link between existing and active functional adult neurogenesis (ANG) and neurodegeneration. The contribution of ANG in AD is not clear and needs to be investigated. By deciphering the mechanisms of ANG in AD brain, we might be able to manipulate endogenous neural progenitors, or control the fate of transplanted neural progenitors towards more efficient cell replacement for AD and other various neurological diseases. Therefore, the information obtained from this work will be fundamental for the design of future neuroreplacement therapies and will benefit the State of California directly.
The overall goal of this project is to test the hypothesis that the brain microenvironment in patients with Alzheimer’s disease (AD) impairs the proliferation of neural stem cells (NSCs) or pluripotent progenitors, and potentially contributes to regional vulnerability to neurodegeneration. In order to test this hypothesis, the applicant puts forward a study plan with three aims. In Specific Aim 1, the applicant proposes to quantify the effects of amyloid deposition neurofibrillary tangle toxicity on adult neurogenesis in vivo, using well-characterized mouse models of AD. In Specific Aim 2, the applicant will isolate hippocampal neural progenitors and use functional genomics to elucidate genetic changes in neural stem cells (NSCs) that are associated with altered SC function during the development and progression of pathology in each of the models. In Specific Aim 3, neurogenesis will be ablated in adult mice and the influence of the loss of neurogenesis will be compared to changes in neurodegeneration and alterations in behavior. It is expected that the results of this project will have direct impact on the design of future neuroreplacement therapies for AD and other neurological disorders. Reviewers recognized that the goal of assessing the degree to which the neuronal microenvironment of AD may affect adult neurogenesis is innovative and interesting. Most of reviewers agreed that there is reasonably good preliminary data suggesting that most of the molecular and cellular techniques are already up and running in the applicant’s laboratory. However, reviewers found the research plan complicated, non-linear, and not very compelling overall. Importantly, they commented that the plan is uncritical: controls, potential pitfalls, and alternative strategies are lacking in the discussion. For example, specific Aim 2 and specific Aim 3 both demand targeted expression of marker proteins to the SC population, however, the GFAP promoter used in both sets of studies will express the marker proteins in all GFAP positive cells. One potential confounding factor in these latter studies is the ability to dissect the influence of the loss of GFAP-positive neural stem cells from the loss of large numbers of brain astrocytes which may also be expected to contribute to alterations in disease progression and functional outcomes, thereby confounding interpretation of the data. In terms of the applicant, reviewers found the applicant’s career development and publication record not as stellar as the top tier respondents to this RFA. A mentoring plan is also in place; however the majority of reviewers found it somewhat vague and not outstanding. In relation to the institution’s commitment, most reviewers agreed that it was very strong. However, there were concerns about the institutional track record and future plans in terms of the extent to which SC research is a high-priority research area at the applicant’s institution. In conclusion, the review panel found the study plan overly complicated without a clear linear path and with major flaws in the research plan. Moreover, neither the candidate nor the institution convinced the reviewers of the value of recommending the proposed study for funding.