Funding Opportunity

THE HUMAN GUT CELL ATLAS

The gastrointestinal (GI) tract is composed of a series of organs joined in a long tube from the mouth to the anus. Food is processed inside the tube, with water and nutrients absorbed and wastes expelled. It is one of the largest interfaces between our body and the surrounding environment. The organs that make up the GI tract are the mouth, esophagus, stomach, small intestine, large intestine, and anus. The gut is the hub of major diseases like Crohn’s disease that affect a specific anatomical region and/or subset of cell types. Therefore, the gut - both small and large intestines - is a critical organ system to pursue in the first draft of the Human Cell Atlas. It is composed of four layers namely, serosa (the outer lining of the intestine), muscularis, submucosa and mucosa (the inner lining of the intestine). Each layer is home for diverse cell types, ranging from the mucus layers that are in contact with the commensal microorganisms, to epithelial cells, muscular, lymphatic, vascular and neuronal components as well as adipose tissue. As part of the Human Cell Atlas, our vision is to catalogue the many cell types in the small and large intestines, including their histological and anatomical organization, understand their interactions and uncover how their dysfunction can lead to Crohn’s disease.

Advances in single-cell and spatial genomics technologies are greatly increasing our ability to interrogate distinct cell types and subpopulations, at the level of the genome, transcriptome and epigenome. These techniques allow access to rare cell types, transient cell states and the influence of tissue architecture and environment. Moreover, the recent development of spatial mapping tools and computational algorithms are now enabling us to construct an unprecedented high-resolution atlas of the gut during development, in healthy homeostasis, and how it changes in chronic disease conditions such as Crohn’s disease.

The creation of the human Gut Cell Atlas (GCA) will allow the Helmsley Charitable Trust to achieve the goals of our Crohn’s Disease Program in determining:

  • the specific cell types in which genetic risk variants for Crohn’s disease act and impact the function of different cells;
  • which cells are affected, and how cell programs are changed during Crohn’s disease;
  • which cell–cell communications are disrupted within specific anatomical structures;
  • what is the effect of a specific therapeutic; and
  • what causes resistance to common therapies.

Thus, there is an urgent need to map the cells of the small and large intestines in their tissue and anatomical contexts and reveal relationships between cell types and states at high resolution. This reference map initially targeted to the ileum and ascending colon will allow us to understand gut development, health, and tackle disease, and will serve as a foundation - analogous to the human genome - for the development of new and effective treatments for Crohn’s disease and other pathologies of the gut.

Project Specifications

As part of the human GCA initiative, we aim to catalogue the many cell types of the gut and understand distinct cell functions and interactions in health and Crohn’s disease. The long-term goal is to support personalized medicine at the cellular level by understanding the link between cell states, tissue function and emergence of disease.

To this end, we are seeking applications to examine defined regions of the gut (terminal ileum, ascending colon) during development, in healthy individuals and in Crohn’s disease subjects from both unaffected and diseased regions. We encourage experts from different disciplines to apply their knowledge of particular cell systems and technologies to the intestine. Applicants should describe data analysis plans and approaches. Areas of interest and suggested techniques addressing molecular, targeted and functional signatures are described below.

Reproducibility, Replicability and Mappability

  • Establish best practices for tissue collection and processing and understand inter-individual variation by comparing different tissue sources (biopsies, resections and post-mortem tissues) and analysis methods; and
  • Lay out a framework for tissue sampling and registration from the gut.

Single Cell Genomic Analysis

  • Unveil gut cell classes and types based on ‘omic signatures by generating cellular, spatial and/or temporal single-cell transcriptomic and/or epigenetic data;
  • Map specific cell types and their spatial locations and interactions while preserving the architecture of the tissue by generating “in situ” histology and anatomical-level imaging data, up to whole organ;
  • Infer networks of interactions between cell types using computational tools, build and apply machine learning algorithms to remap the gut across individuals in health and Crohn’s disease; and
  • Determine microenvironment, tissue composition and ratio of numerous cell types (e.g., epithelial cells, vascular cells, immune cells, progenitor cells, fat cells, smooth muscle cells, etc.) in the various layers of the gut and how these ratios are perturbed during Crohn’s disease.

Targeted approaches

  • Study specific cell lineages (e.g., immune, nervous, epithelial, etc.) by generating spatially defined single cell transcriptome, epigenetic or immuno-histological data;
  • Examine stem cell behavior and differentiation markers by generating intestinal organoids, and exploring and analyzing single cells derived from them; and
  • Define functional activity for specific subsets of cells (secretory, absorptive, immune, contractile, environmental sensing and response, etc.) in health and Crohn’s disease.

APPLICATION PROCESS

Key Dates

9/18/2018:       Application portal opens

11/13/2018:     Applications due by 5:00 PM PT

3/11/2019:       Full proposals due by 5:00 PM ET (subject to change)

7/1/2019:         Earliest start date of project

Application Requirements

All applications for the Helmsley Charitable Trust (Helmsley) human Gut Cell Atlas (GCA) must be completed and submitted through the Chan Zuckerberg Initiative’s online grants management portal at https://apply.chanzuckerberg.com. It is recommended that applicants familiarize themselves with this portal well in advance of any deadlines. Detailed application instructions are available at https://www.chanzuckerberg.com/science/rfa/seed-networks/instructions, as well as in the grants management portal at https://apply.chanzuckerberg.com/.

Applicants may request $250,000-$1,000,000 annually for up to three years. Projects may be proposed for less than three years in duration but may not exceed three years (with total requests ranging from $750K-$3,000,000).

The application consists of the following sections:

  • Applicant Details (Part 1 and Part 2): Information about the Principal Investigator (PI)
  • Organization Details for PI
  • Project Details
  1. Project Title
  2. Full paper or preprint citations (with PubMed or bioRxiv links), GitHub repository links, data repositories, and/or similar documentation for up to five of the most significant contributions members of the grant have made that are relevant to the proposal.
  3. Abstract/Project Summary ​(Lay description of the project; 250 words maximum).
  4. List of Co-Principal Investigators​ and individual statements from each co-PI describing their specific contributions (750 words maximum per co-PI, if applicable)
  • Project Proposal
  1. Abstract: ​ Description of the GCA research program (250 words maximum;)
  2. Proposal Body: ​ (2000 words maximum). Should include two parts:

    Outline clearly the hypothesis and the goals of the project and its relevance to the creation of a healthy reference atlas for the ileum and colon and to Crohn’s Disease. Describe the impact this study could have on Crohn’s disease research whether short-term or long-term.

    Explain the overall concept and challenges the proposal seeks to address. Describe clearly the research strategy to be employed, main milestones, expected outcomes, and deliverables.
  3. Figures​ (optional): limited to one page, inclusive of legends.
  4. References​ cited in your proposal (no word/page limit).
  • Brief preliminary budget (one page per PI, maximum): Application budgets must reflect the actual needs of the proposed project within your group. Helmsley will work closely with successful applicants to reach a mutually acceptable budget after review.
  • Biosketches​ for PI and all co-PIs listed above (five pages maximum per biosketch, NIH format or similar).
  • Letter of commitment: Include a signed commitment letter from each co-PI and/or collaborator

The proposal, biosketches, brief preliminary budgets, and letters of commitment must be uploaded in PDF format. All text in these documents must be in Arial 11-point font or larger and no less than single spaced with minimum of half inch margins on all sides.

The formatting and component requirements, including word and page limits indicated above, will be enforced by the review team. Any submitted materials that exceed the word and page limits or do not follow the requirements will not be considered during the application review process.

Helmsley strongly suggests that investigators consult their home institution to determine eligibility to apply for this grant and institutional policy on indirect costs. (See below for guidance on Helmsley’s policies.)

ELIGIBILITY

Helmsley seeks the best possible solutions for the funding opportunity described in this RFA and welcomes applications from the U.S.; international-based nonprofit organizations (including institutions of higher education, public charities, hospitals, and government agencies); and combinations of the aforementioned organizations. Individuals are not eligible to apply. Additionally, applicants who have developed tools and resources for other organ systems and diseases and could leverage this experience for Crohn’s disease are encouraged to apply. Helmsley envisions creating, through these grants and their investigators, the nucleus of a GCA community. We will work to align the various proposals to synergistically build a cohesive model of the human gut.  We will convene face to face meetings (at least 2 per year) for all members of the consortium to meet and share best practices, knowledge, progress and challenges.

  • Applicants must hold a PhD, MD or equivalent Computer Science or Engineering degree.
  • Applicants must have an independent faculty position or equivalent at an accredited college, university, medical school, or other research facility.
  • All grants will be made in compliance with the US Treasury Department’s Office of Foreign Asset Control (OFAC) program. For additional information regarding OFAC sanctions, please refer to the US Treasury Department’s resources located here: https://www.treasury.gov/resource-center/sanctions/Pages/default.aspx.
  • All funding decisions are at the sole discretion of Helmsley and its Board of Trustees.

Tax Status: Helmsley generally funds public charities classified as either a Section 509(a)(1) or 509(a)(2) organization. Helmsley does not typically fund Section 509(a)(3) type iii supporting organizations. Organizations with a 509(a)(3) classification are encouraged to contact us for further discussion with a Grants Manager. International nonprofit organizations must complete additional documentation/submit additional materials for Helmsley’s review before a grant is approved. If applicable, applicants will receive further instructions that will explain the information Helmsley requires.

For questions about eligibility, please contact us in advance of the proposal deadline at contact GCAgrants@helmsleytrust.org. Deadline extensions will not be granted.

SELECTION PROCESS

Helmsley will evaluate all RFA applications for scientific merit and submit them for review by a panel of research and industry experts (appropriate conflict of interest and confidentiality protections will be put in place). The RFA application is considered a pre-proposal and selected projects will be invited to submit a Full Proposal.  

Selection of awardees will be based on:

  • The quality of the proposal, expertise, and capacity of the investigator(s) for addressing the proposed project and the project’s relevance to Crohn’s disease;
  • Interest and potential impact of the questions being addressed in the proposal for the development and/or production of valuable data sets, computational tools, or methods for the GCA; and
  • Flexibility of the investigator and contributions of the proposal to establish a cohesive GCA that will serve as a key reference for the field.

​Helmsley will perform appropriate due diligence before a grant is awarded. Selected applications will be recommended for funding by Helmsley’s Crohn’s Disease Program staff in consultation with our scientific advisors and final funding decisions will be made by Helmsley’s Board of Trustees. There is no expectation of any specific number of awards, and Helmsley reserves the right to not recommend the funding of any applications. Helmsley does not provide feedback on decisions for unfunded proposals.

POLICIES AND GRANT TERMS  

Use of Grant Funds: The proposal and budget, grant term, and payment schedule will be included in the grant agreement letter. This will ensure clarity regarding what both parties agree to as the project scope and timing. During the life of a grant, Helmsley prefers an open dialogue regarding proposed changes to the budget. Budget modifications require written approval by Helmsley. Unused research funds may be carried over to the following year and requests for no-cost extensions will be considered.

Intellectual Property: If grantees expect to develop intellectual property during a grant term, the grant agreement letter requires that grantees make an effort to license out findings within 24 months, or Helmsley will discuss an appropriate timeline for its commercialization.

Reporting: If approved for funding, the grant agreement letter will delineate the grant period and reporting timeline. All reports should be submitted on time and online. No further payments will be made if reports are outstanding. Specific deliverable requirements will be outlined in the award notification. Investigators of funded projects will be required to participate in regular investigator meetings (expected to be bi-annual face to face meetings). Costs of this travel and other GCA related travel should be allocated from the grant funds and included in the project budget.

Indemnification: Grantee organizations will be asked in the agreement to defend, indemnify and hold harmless Helmsley, its Trustees, officers, employees and agents.

Indirect Costs: Grantee organizations with operating budgets under $5 million may request up to 20% of the total project budget for indirect costs and organizations with operating budgets over $5 million may request up to 10% in indirect costs. Indirect costs on the first $20,000 of equipment and $25,000 of subcontractors, respectively, are allowed within the general ceiling (10%) to a respective limit of $2,000 and $2,500. Helmsley will discuss indirect costs with grantees if the grant is a capital or endowment request.

Grant Agreement Letter: If an organization is awarded a grant from Helmsley, grantees will receive Helmsley’s standard grant agreement letter. Grant agreement letters are binding, comprehensive, and all inclusive; therefore, grantees should read all terms and conditions prior to signing. Grantees are welcome to inquire about the clause(s) that elicit(s) any questions or concerns, but please be aware that Helmsley only modifies terms when (in rare instances) our terms conflict with a local law to which a grantee is bound.

Grant Modifications: Helmsley views its grantees as partners in achieving program goals, and to have a successful partnership, communication is vital. If a grant is awarded, Helmsley expects that grantees will maintain an open dialogue with program staff about potential changes in scope of work, grant amount, reallocation of expense categories, no cost extensions or carryovers. All budget modifications of more than $15,000 of an annual payment require prior written permission from Helmsley. If grantees need to carryover funds from one year to the next, any carryover of more than $15,000 requires approval. Also, no change in scope or grant term can be made without prior written approval from Helmsley.

Non-Discrimination and Proselytizing: Helmsley’s agreement includes a non-discrimination clause to ensure that all potential recipients of and participants in a grantee’s programs and services have access and receive services without regard to race, sex, education, ethnicity, socio-economic status, religion, ability/disability, sexual orientation, gender self-identification, age, country of origin, first language, marital status or citizenship. No funds from Helmsley may be used to proselytize directly or indirectly on behalf of any religious faith, doctrine or belief.

Data Sharing:  One of Helmsley’s goals in funding selected research projects is to have all data and biospecimens generated from funded research be made available in the manner most conducive to furthering scientific research.  The grant agreement letter will include specific requirements in alignment with this goal, including, as appropriate, requirements that deidentified data and biospecimens be maintained and be made publicly available for future research.

CONFIDENTIALITY

All submitted applications will be kept confidential to the greatest extent possible, except as necessary for evaluation or to comply with any applicable laws. After the grant award, funded proposals will be shared across the GCA consortium, but unfunded proposals will remain confidential. Application materials will not be returned to applicants.

PUBLICITY

In the event that an organization is chosen to receive a grant and wishes to publicize it using Helmsley’s name, Helmsley must approve any publicity that the grantee seeks to initiate or issue. This is covered in the “Acknowledgement, Publicity, Publication, and Communication with Media” section of Helmsley’s grant agreement letter. You may also visit Helmsley’s Grantee Resources Page to learn more about guidelines for using Helmsley’s name.

RFA CONTACT

For programmatic inquiries, or other questions pertaining to this RFA, please contact GCAgrants@helmsleytrust.org